1,3-diaza-spiro-[3.4]-octane derivatives

ABSTRACT

The invention relates to 1,3-diaza-spiro-[3.4]-octane derivatives, their preparation and use in medicine, particularly in various neurological disorders, including but not limited to pain, neurodegenerative disorders, neuroinflammatory disorders, neuropsychiatric disorders, substance abuse/dependence.

This application claims priority of European Patent Application No.17020299.8, filed Jul. 12, 2017, the contents of which are incorporatedherein by reference.

The invention relates to 1,3-diaza-spiro-[3.4]-octane derivatives, theirpreparation and use in medicine, particularly in various neurologicaldisorders, including but not limited to pain, neurodegenerativedisorders, neuroinflammatory disorders, neuropsychiatric disorders,substance abuse/dependence.

Opioid receptors are a group of Gi/o protein-coupled receptors which arewidely distributed in the human body. The opioid receptors are currentlysubdivided into four major classes, i.e. the three classical opioidreceptors mu-opioid (MOP) receptor, kappa-opioid (KOP) receptor, anddelta-opioid (DOP) receptor as well as the opioid receptor-like (ORL-1)receptor, which was more recently discovered based on its high homologywith said classical opioid receptors. After identification of theendogenous ligand of the ORL-1 receptor, known as nociceptin/orphaninFQ, a highly basic 17 amino acid peptide isolated from tissue extractsin 1995, the ORL-1 receptor was renamed “nociceptin opioid peptidereceptor” and abbreviated as “NOP-receptor”.

The classical opioid receptors (MOP, KOP and DOP) as well as the NOPreceptor are widely distributed/expressed in the human body, includingin the brain, the spinal cord, on peripheral sensory neurons and theintestinal tract, wherein the distribution pattern differs between thedifferent receptor classes.

Nociceptin acts at the molecular and cellular level in very much thesame way as opioids. However, its pharmacological effects sometimesdiffer from, and even oppose those of opioids. NOP-receptor activationtranslates into a complex pharmacology of pain modulation, which,depending on route of administration, pain model and species involved,leads to either pronociceptive or antinociceptive activity. Furthermore,the NOP receptor system is upregulated under conditions of chronic pain.Systemic administration of selective NOP receptor agonists was found toexert a potent and efficacious analgesia in non-human primate models ofacute and inflammatory pain in the absence of side effects. Theactivation of NOP receptors has been demonstrated to be devoid ofreinforcing effects but to inhibit opioid-mediated reward in rodents andnon-human primates (Review: Schroeder et al, Br J Pharmacol 2014; 171(16): 3777-3800, and references therein).

Besides the involvement of the NOP receptor in nociception, results frompreclinical experiments suggest that NOP receptor agonists might beuseful inter alia in the treatment of neuropsychiatric disorders (Witkinet al, Pharmacology & Therapeutics, 141 (2014) 283-299; Jenck et al.,Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858). Remarkably, the DOPreceptor is also implicated to modulate not only pain but alsoneuropsychiatric disorders (Mabrouk et al, 2014; Pradhan et al., 2011).

Strong opioids acting at the MOP receptor site are widely used to treatmoderate to severe acute and chronic pain. However, the therapeuticwindow of strong opioids is limited by severe side effects such asnausea and vomiting, constipation, dizziness, somnolence, respiratorydepression, physical dependence and abuse. Furthermore, it is known thatMOP receptor agonists show only reduced effectiveness under conditionsof chronic and neuropathic pain.

It is known that some of the above mentioned side-effects of strongopioids are mediated by activation of classic opioid-receptors withinthe central nervous system. Furthermore, peripheral opioid receptors,when activated, can inhibit transmission of nociceptive signals shown inboth, clinical and animal studies (Gupta et al., 2001; Kalso et al.,2002; Stein et al., 2003; Zollner et al., 2008).

Thus, to avoid CNS-mediated adverse effects after systemicadministration, one approach has been to provide peripherally restrictedopioid receptor ligands that do not easily cross the blood-brain barrierand therefore distribute poorly to the central nervous system (see forinstance WO 2015/192039). Such peripherally acting compounds mightcombine effective analgesia with limited side-effects.

Another approach has been to provide compounds which interact with boththe NOP receptor and the MOP receptor. Such compounds have for instancebeen described in WO 2004/043967, WO 2012/013343 and WO 2009/118168.

A further approach has been to provide multi-opioid receptor analgesicsthat modulate more than one of the opioid receptor subtypes to provideadditive or synergistic analgesia and/or reduced side effects like abuseliability or tolerance.

On the one hand, it would be desirable to provide analgesics thatselectively act on the NOP receptor system but less pronounced on theclassic opioid receptor system, especially MOP receptor system, whereasit would be desirable to distinguish between central nervous activityand peripheral nervous activity. On the other hand, it would bedesirable to provide analgesics that act on the NOP receptor system andalso to a balanced degree on the MOP receptor system, whereas it wouldbe desirable to distinguish between central nervous activity andperipheral nervous activity.

There is a need for medicaments which are effective in the treatment ofpain and which have advantages compared to the compounds of the priorart. Where possible, such medicaments should contain such a small doseof active ingredient that satisfactory pain therapy can be ensuredwithout the occurrence of intolerable treatment-emergent adverse events.

It is an object of the invention to provide pharmacologically activecompounds, preferably analgesics that have advantages compared to theprior art.

This object has been achieved by the subject-matter of the patentclaims.

A first aspect of the invention relates to 1,3-diaza-spiro-[3.4]-octanederivatives according to general formula (I)

whereinR¹ and R² independently of one another mean

-   -   —H;    -   —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,        unsubstituted or substituted with one, two, three or four        substituents independently of one another selected from the        group consisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and        —CO₂CH₃;    -   a 3-12-membered cycloalkyl moiety, saturated or unsaturated,        unsubstituted or substituted with one, two, three or four        substituents independently of one another selected from the        group consisting of —F, —Cl, —Br, —I, —OH,    -   —OCH₃, —CN and —CO₂CH₃; wherein said 3-12-membered cycloalkyl        moiety is optionally connected through —C₁-C₆-alkylene-, linear        or branched, saturated or unsaturated, unsubstituted; or    -   a 3-12-membered heterocycloalkyl moiety, saturated or        unsaturated, unsubstituted or substituted with one, two, three        or four substituents independently of one another selected from        the group consisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and        —CO₂CH₃; wherein said 3-12-membered heterocycloalkyl moiety is        optionally connected through —C₁-C₆-alkylene-, linear or        branched, saturated or unsaturated, unsubstituted;        or        R¹ and R² together with the nitrogen atom to which they are        attached form a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or        —(CH₂)₂—NR^(A)—(CH₂)₂—, wherein R^(A) means —H or —C₁-C₆-alkyl,        linear or branched, saturated or unsaturated, unsubstituted or        substituted with one, two, three or four substituents        independently of one another selected from the group consisting        of —F, —Cl, —Br and —I;        preferably with the proviso that R¹ and R² do not simultaneously        mean —H;        R³ means    -   —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,        unsubstituted, mono- or polysubstituted;    -   a 3-12-membered cycloalkyl moiety, saturated or unsaturated,        unsubstituted, mono- or polysubstituted; wherein said        3-12-membered cycloalkyl moiety is optionally connected through        —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,        unsubstituted, mono- or polysubstituted;    -   a 3-12-membered heterocycloalkyl moiety, saturated or        unsaturated, unsubstituted, mono- or polysubstituted; wherein        said 3-12-membered heterocycloalkyl moiety is optionally        connected through —C₁-C₆-alkylene-, linear or branched,        saturated or unsaturated, unsubstituted, mono- or        polysubstituted;    -   a 6-14-membered aryl moiety, unsubstituted, mono- or        polysubstituted; wherein said 6-14-membered aryl moiety is        optionally connected through —C₁-C₆-alkylene-, linear or        branched, saturated or unsaturated, unsubstituted, mono- or        polysubstituted; or    -   a 5-14-membered heteroaryl moiety, unsubstituted, mono- or        polysubstituted; wherein said 5-14-membered heteroaryl moiety is        optionally connected through —C₁-C₆-alkylene-, linear or        branched, saturated or unsaturated, unsubstituted, mono- or        polysubstituted;        R⁴ means    -   —H;    -   —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,        unsubstituted, mono- or polysubstituted; wherein said        —C₁-C₆-alkyl is optionally connected through —C(═O)—, —C(═O)O—,        or —S(═O)₂—;    -   a 3-12-membered cycloalkyl moiety, saturated or unsaturated,        unsubstituted, mono- or polysubstituted; wherein said        3-12-membered cycloalkyl moiety is optionally connected through        —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,        unsubstituted, mono- or polysubstituted; or wherein said        3-12-membered cycloalkyl moiety is optionally connected through        —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—;    -   a 3-12-membered heterocycloalkyl moiety, saturated or        unsaturated, unsubstituted, mono- or polysubstituted; wherein        said 3-12-membered heterocycloalkyl moiety is optionally        connected through —C₁-C₆-alkylene-, linear or branched,        saturated or unsaturated, unsubstituted, mono- or        polysubstituted; or wherein said 3-12-membered heterocycloalkyl        moiety is optionally connected through —C(═O)—, —C(═O)O—,        —C(═O)O—CH₂—, or —S(═O)₂—;    -   a 6-14-membered aryl moiety, unsubstituted, mono- or        polysubstituted; wherein said 6-14-membered aryl moiety is        optionally connected through —C₁-C₆-alkylene-, linear or        branched, saturated or unsaturated, unsubstituted, mono- or        polysubstituted; or wherein said 6-14-membered aryl moiety is        optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or        —S(═O)₂—; or    -   a 5-14-membered heteroaryl moiety, unsubstituted, mono- or        polysubstituted; wherein said 5-14-membered heteroaryl moiety is        optionally connected through —C₁-C₆-alkylene-, linear or        branched, saturated or unsaturated, unsubstituted, mono- or        polysubstituted; or wherein said 5-14-membered heteroaryl moiety        is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—,        or —S(═O)₂—;        R⁵ means    -   —H;    -   —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,        unsubstituted, mono- or polysubstituted; wherein said        —C₁-C₆-alkyl is optionally connected through —C(═O)—, —C(═O)O—,        or —S(═O)₂—;    -   a 3-12-membered cycloalkyl moiety, saturated or unsaturated,        unsubstituted, mono- or polysubstituted; wherein said        3-12-membered cycloalkyl moiety is optionally connected through        —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,        unsubstituted, mono- or polysubstituted; or wherein said        3-12-membered cycloalkyl moiety is optionally connected through        —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—;    -   a 3-12-membered heterocycloalkyl moiety, saturated or        unsaturated, unsubstituted, mono- or polysubstituted; wherein        said 3-12-membered heterocycloalkyl moiety is optionally        connected through —C₁-C₆-alkylene-, linear or branched,        saturated or unsaturated, unsubstituted, mono- or        polysubstituted; or wherein said 3-12-membered heterocycloalkyl        moiety is optionally connected through —C(═O)—, —C(═O)O—,        —C(═O)O—CH₂—, or —S(═O)₂—;    -   a 6-14-membered aryl moiety, unsubstituted, mono- or        polysubstituted; wherein said 6-14-membered aryl moiety is        optionally connected through —C₁-C₆-alkylene-, linear or        branched, saturated or unsaturated, unsubstituted, mono- or        polysubstituted; or wherein said 6-14-membered aryl moiety is        optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or        —S(═O)₂—; or    -   a 5-14-membered heteroaryl moiety, unsubstituted, mono- or        polysubstituted; wherein said 5-14-membered heteroaryl moiety is        optionally connected through —C₁-C₆-alkylene-, linear or        branched, saturated or unsaturated, unsubstituted, mono- or        polysubstituted; or wherein said 5-14-membered heteroaryl moiety        is optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—,        or —S(═O)₂—;        R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ independently of one another mean        —H, —F, —Cl, —Br, —I, —OH, or —C₁-C₆-alkyl, linear or branched,        saturated or unsaturated, unsubstituted, mono- or        polysubstituted;        or        R⁶ and R⁷ together mean ═O;        wherein “mono- or polysubstituted” means that one or more        hydrogen atoms are replaced by a substituent independently of        one another selected from the group consisting of —F, —Cl, —Br,        —I, —CN, —R¹², —C(═O)R¹², —C(═O)OR¹², —C(═O)NR¹²R¹³,        —O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀—CH₃, ═O, —OR¹²,        —OC(═O)R¹², —OC(═O)OR¹², —OC(═O)NR¹²R¹³, —NO₂, —NR¹²R¹³,        —NR¹²—(CH₂)₁₋₆—C(═O)R¹³, —NR¹²—(CH₂)₁₋₆—C(═O)OR¹³,        —NR¹⁴—(CH₂)₁₋₆—C(═O)NR¹²R¹³, —NR¹²C(═O)R¹³, —NR¹²C(═O)—OR¹³,        —NR¹⁴C(═O)NR¹²R¹³, —NR¹²S(═O)₂R¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹²,        —S(═O)₂OR¹², and —S(═O)₂NR¹²R¹³;        wherein        R¹², R¹³ and R¹⁴ independently of one another mean    -   —H;    -   —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,        unsubstituted or substituted with one, two, three or four        substituents independently of one another selected from the        group consisting of —F, —Cl, —Br, —I, —CN, ═O, —OH, —NH₂,        —NH—C₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —C₁-C₆-alkyl, —O—C₁-C₆-alkyl,        —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NH—C₁-C₆-alkyl,        —C(═O)N(C₁-C₆-alkyl)₂, —S—C₁-C₆-alkyl, —S(═O)—C₁-C₆-alkyl and        —S(═O)₂—C₁-C₆-alkyl;    -   a 3-12-membered cycloalkyl moiety, saturated or unsaturated,        unsubstituted, mono- or polysubstituted; wherein said        3-12-membered cycloalkyl moiety is optionally connected through        —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,        unsubstituted or substituted with one, two, three or four        substituents independently of one another selected from the        group consisting of —F, —Cl, —Br, —I, —CN, ═O, —OH, —NH₂,        —NH—C₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —C₁-C₆-alkyl, —O—C₁-C₆-alkyl,        —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NH—C₁-C₆-alkyl,        —C(═O)N(C₁-C₆-alkyl)₂, —S—C₁-C₆-alkyl, —S(═O)—C₁-C₆-alkyl and        —S(═O)₂—C₁-C₆-alkyl;    -   a 3-12-membered heterocycloalkyl moiety, saturated or        unsaturated, unsubstituted, mono- or polysubstituted; wherein        said 3-12-membered heterocycloalkyl moiety is optionally        connected through —C₁-C₆-alkylene-, linear or branched,        saturated or unsaturated, unsubstituted or substituted with one,        two, three or four substituents independently of one another        selected from the group consisting of —F, —Cl, —Br, —I, —CN, ═O,        —OH, —NH₂, —NH—C₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —C₁-C₆-alkyl,        —O—C₁-C₆-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂,        —C(═O)NH—C₁-C₆-alkyl, —C(═O)N(C₁-C₆-alkyl)₂, —S—C₁-C₆-alkyl,        —S(═O)—C₁-C₆-alkyl and —S(═O)₂—C₁-C₆-alkyl;    -   a 6-14-membered aryl moiety, unsubstituted, mono- or        polysubstituted; wherein said 6-14-membered aryl moiety is        optionally connected through —C₁-C₆-alkylene-, linear or        branched, saturated or unsaturated, unsubstituted or substituted        with one, two, three or four substituents independently of one        another selected from the group consisting of —F, —Cl, —Br, —I,        —CN, ═O, —OH, —NH₂, —NH—C₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂,        —C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl,        —C(═O)NH₂, —C(═O)NH—C₁-C₆-alkyl, —C(═O)N(C₁-C₆-alkyl)₂,        —S—C₁-C₆-alkyl, —S(═O)—C₁-C₆-alkyl and —S(═O)₂—C₁-C₆-alkyl; or    -   a 5-14-membered heteroaryl moiety, unsubstituted, mono- or        polysubstituted; wherein said 5-14-membered heteroaryl moiety is        optionally connected through —C₁-C₆-alkylene-, linear or        branched, saturated or unsaturated, unsubstituted or substituted        with one, two, three or four substituents independently of one        another selected from the group consisting of —F, —Cl, —Br, —I,        —CN, ═O, —OH, —NH₂, —NH—C₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂,        —C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl,        —C(═O)NH₂, —C(═O)NH—C₁-C₆-alkyl,    -   —C(═O)N(C₁-C₆-alkyl)₂, —S—C₁-C₆-alkyl, —S(═O)—C₁-C₆-alkyl and        —S(═O)₂—C₁-C₆-alkyl;    -   or R¹² and R¹³ within —C(═O)NR¹²R¹³, —OC(═O)NR¹²R¹³, —NR¹²R¹³,        —NR¹⁴—(CH₂)₁₋₆—C(═O)NR¹²R¹³, —NR¹⁴C(═O)—NR¹²R¹³, or        —S(═O)₂NR¹²R¹³ together with the nitrogen atom to which they are        attached form a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or        —(CH₂)₂—NR^(B)—(CH₂)₂—, wherein R^(B) means —H or —C₁-C₆-alkyl,        linear or branched, saturated or unsaturated, unsubstituted or        substituted with one, two, three or four substituents        independently of one another selected from the group consisting        of —F, —Cl, —Br and —I;    -   or a physiologically acceptable salt thereof.

Preferably, aryl includes but is not limited to phenyl and naphthyl.Preferably, heteroaryl includes but is not limited to -1,2-benzodioxole,-pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl,-imidazolyl, -benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl,-benzothiazolyl, -oxazolyl, -benzoxazolyl, -pyrazolyl, -quinolinyl,-isoquinolinyl, -quinazolinyl, -indolyl, -indolinyl,-benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl, or-1H-pyrrolo[2,3-b]pyridinyl. Preferably, cycloalkyl includes but is notlimited to -cyclopropyl, -cyclobutyl,

-   -   cyclopentyl and -cyclohexyl. Preferably, heterocycloalkyl        includes but is not limited to -aziridinyl, -azetidinyl,        -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl,        -sulfamorpholinyl, -oxiridinyl, -oxetanyl, -tetrahydropyranyl,        and -pyranyl.

When a moiety is connected through an asymmetric group such as —C(═O)O—or —C(═O)O—CH₂—, said asymmetric group may be arranged in eitherdirection. For example, when R⁴ is connected to the core structurethrough —C(═O)O—, the arrangement may be either R⁴—C(═O)O-core orcore-C(═O)O—R⁴.

In a preferred embodiment, R⁶ and R⁷ together mean ═O such that the fivemembered ring is a hydantoin; and/or R⁸, R⁹, R¹⁰, and R¹¹ independentlyof one another mean —H, —F, —OH, or —C₁-C₆-alkyl; preferably —H.

In preferred embodiments of the compound according to the invention, R⁶,R⁷, R⁸, R⁹, R¹⁰, and R¹¹ independently of one another mean —H, —F, —OH,or —C₁-C₆-alkyl; preferably —H.

In a preferred embodiment of the compound according to the invention, R¹means —H; and R² means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted. Preferably, R¹means —H and R² means —CH₃.

In another preferred embodiment of the compound according to theinvention, R¹ means —CH₃; and R² means —C₁-C₆-alkyl, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted.Preferably, R¹ means —CH₃ and R² means —CH₃.

In still another preferred embodiment of the compound according to theinvention, R¹ and R² together with the nitrogen atom to which they areattached form a ring and mean —(CH₂)₃₋₆—. Preferably, R¹ and R² togetherwith the nitrogen atom to which they are attached form a ring and mean—(CH₂)₃— or —(CH₂)₄—.

In another preferred embodiment,

-   -   R¹ means —H or —CH₃; and    -   R² means a 3-12-membered cycloalkyl moiety, saturated or        unsaturated, unsubstituted; preferably -cycloalkyl, -cyclobutyl        or -cyclopentyl; or R² means a 3-12-membered heterocycloalkyl        moiety, saturated or unsaturated, unsubstituted; preferably        -oxetanyl or -tetrahydrofuranyl.

In yet another preferred embodiment,

-   -   R¹ means —H or —CH₃; and    -   R² means a 3-12-membered cycloalkyl moiety, saturated or        unsaturated, unsubstituted; wherein said 3-12-membered        cycloalkyl moiety is connected through —CH₂—, unsubstituted;        preferably —CH₂-cycloalkyl, —CH₂— cyclobutyl or        —CH₂-cyclopentyl; or R² means a 3-12-membered heterocycloalkyl        moiety, saturated or unsaturated, unsubstituted; wherein said        3-12-membered heterocycloalkyl moiety is connected through        —CH₂—, unsubstituted; preferably —CH₂-oxetanyl or        —CH₂-tetrahydrofuranyl.

In a preferred embodiment of the compound according to the invention, R³means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted. Preferably, R³ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or monosubstituted with —OCH₃.

In another preferred embodiment of the compound according to theinvention, R³ means a 6-14-membered aryl moiety, unsubstituted, mono- orpolysubstituted, optionally connected through —C₁-C₆-alkylene-, linearor branched, saturated or unsaturated, unsubstituted. In a preferredembodiment, R³ means -phenyl unsubstituted, mono- or polysubstituted.More preferably, R³ means -phenyl unsubstituted, mono-, di- ortrisubstituted with —F; —Cl; —Br; —C₁-C₄-alkyl, preferably —CH₃; —CF₃;—CHF₂; —CH₂F; —CN; —OH; —OC₁-C₄-alkyl, preferably —OCH₃; —OCF₃ or—OCH₂OCH₃; preferably —F. Preferably, R³ means -phenyl unsubstituted or-phenyl monosubstituted with —F. In another preferred embodiment, R³means -benzyl unsubstituted, mono- or polysubstituted. More preferably,R³ means -benzyl unsubstituted, mono-, di- or trisubstituted with —F;—Cl; —Br; —C₁-C₄-alkyl, preferably —CH₃; —CF₃; —CHF₂; —CH₂F; —CN; —OH;—OC₁-C₄-alkyl, preferably —OCH₃; —OCF₃ or —OCH₂OCH₃; preferably —F.

In still another preferred embodiment of the compound according to theinvention, R³ means a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted. Preferably, R³ means -thienyl or -pyridinyl,in each case unsubstituted, mono- or polysubstituted. More preferably,R³ means -thienyl, -pyridinyl, -imidazolyl or benzimidazolyl, in eachcase unsubstituted, mono-, di- or trisubstituted with —F; —Cl; —Br;—C₁-C₄-alkyl, preferably —CH₃; —CF₃; —CHF₂; —CH₂F; —CN; —OH;—OC₁-C₄-alkyl, preferably —OCH₃; —OCF₃ or —OCH₂OCH₃; preferably —F.

In a preferred embodiment of the compound according to the invention, R⁴means —H.

In another preferred embodiment of the compound according to theinvention, R⁴ means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁴means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or monosubstituted with a substituent selected from thegroup consisting of —F, —Cl, —Br, —I, —CN, —CF₃, —OH, —O—C₁-C₄-alkyl,—OCF₃, —O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀—CH₃, —OC(═O)C₁-C₄-alkyl,—C(═O)C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂,

—C(═O)NHC₁-C₄-alkyl, —C(═O)NHC₁-C₄-alkylene-CN,—C(═O)NHC₁-C₄-alkylene-O—C₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂;—S(═O)C₁-C₄-alkyl, and —S(═O)₂C₁-C₄-alkyl; or with —C(═O)NR¹²R¹³ whereinR¹² and R¹³ together with the nitrogen atom to which they are attachedform a ring and mean —(CH₂)₃₋₆—, —(CH₂)₂—O—(CH₂)₂—, or—(CH₂)₂—NR^(B)—(CH₂)₂—, wherein R^(B) means —H or —C₁-C₆-alkyl; or with—C(═O)NH-3-12-membered cycloalkyl, saturated or unsaturated,unsubstituted or monosubstituted with —F, —Cl, —Br, —I, —CN, or —OH; orwith —C(═O)NH-3-12-membered heterocycloalkyl, saturated or unsaturated,unsubstituted or monosubstituted with —F, —Cl, —Br, —I, —CN, or —OH.More preferably, R⁴ means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted or monosubstituted with —O—C₁-C₄-alkyl or—C(═O)N(C₁-C₄-alkyl)₂.

In still another preferred embodiment of the compound according to theinvention, R⁴ means a 3-12-membered cycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted; wherein the3-12-membered cycloalkyl moiety is connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted. Preferably, R⁴ means a 3-12-membered cycloalkyl moiety,saturated or unsaturated, unsubstituted, mono- or polysubstituted;preferably cyclopropyl or cyclobutyl; wherein said 3-12-memberedcycloalkyl moiety is connected through —CH₂— or —CH₂CH₂—. Morepreferably, R⁴ means a 3-12-membered cycloalkyl moiety, saturated orunsaturated, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl,—C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl,—C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl; whereinsaid 3-12-membered cycloalkyl moiety is connected through —CH₂— or—CH₂CH₂—. Preferably, R⁴ means cyclopropyl, optionally monosubstitutedwith —F or —OH, and connected through —CH₂—, or cyclobutyl, optionallymonosubstituted with —F or —OH, and connected through —CH₂—.

In a preferred embodiment of the compound according to the invention, R⁴means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted. Preferably, R⁴ means a 3-12-membered heterocycloalkylmoiety, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; wherein said 3-12-membered heterocycloalkyl moiety isconnected through —CH₂— or —CH₂CH₂—. More preferably, R⁴ means-oxetanyl, -tetrahydrofuranyl or -tetrahydropyranyl, in each caseunsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH,—C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl,—C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl; whereinsaid -oxetanyl, -tetrahydrofuranyl or -tetrahydropyranyl is connectedthrough —CH₂— or —CH₂CH₂—. Preferably, R⁴ means oxetanyl, optionallymonosubstituted with —F, and connected through —CH₂—

In yet another preferred embodiment of the compound according to theinvention, R⁴ means a 6-14-membered aryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 6-14-membered aryl moiety is connectedthrough —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted. Preferably, R⁴ means -phenyl,unsubstituted, mono- or polysubstituted; wherein said -phenyl isconnected through —CH₂— or —CH₂CH₂—. More preferably, R⁴ means -phenyl,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH,—C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl,

—C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl; whereinsaid -phenyl is connected through —CH₂— or —CH₂CH₂—.

In a further preferred embodiment of the compound according to theinvention, R⁴ means a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted; wherein said 5-14-membered heteroaryl moietyis connected through —C₁-C₆-alkylene-, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted. Preferably, R⁴means a 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said -phenyl is connected through —CH₂— or—CH₂CH₂—. More preferably, R⁴ means -pyridinyl, -pyrimidinyl,-pyrazinyl, or -pyrazolinyl, in each case unsubstituted or substitutedwith one, two, three or four substituents independently of one anotherselected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH,—C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂,—C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and—S(═O)₂C₁-C₄-alkyl; wherein said -pyridinyl, -pyrimidinyl, -pyrazinyl,or -pyrazolinyl is connected through —CH₂— or —CH₂CH₂—.

In a preferred embodiment of the compound according to the invention, R⁵means —H.

In another preferred embodiment of the compound according to theinvention, R⁵ means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, —OH, —O—C₁-C₄-alkyl,—O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀—CH₃, —C(═O)OH,—C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl,—C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl.Preferably, R⁵ means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted or monosubstituted with —F, —Cl, —Br, —I,—CN, —OH, —O—C₁-C₄-alkyl, —O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀—CH₃,—C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkylor —S(═O)₂C₁-C₄-alkyl. Preferably, R⁵ is selected from the groupconsisting of —CH₂—C(═O)NH₂, —CH₂CH₂—S(═O)₂CH₃, —CH₂C(CH₃)₂OCH₃, and—CH₂CH₂CN.

In particularly preferred embodiments of the compound according to theinvention, R⁵ means —C₁-C₆-alkyl-(C═O)NR¹²R¹³,—C₁-C₆-alkyl-OC(═O)NR¹²R¹³, —C₁-C₆-alkyl-NR¹²R¹³,—C₁-C₆-alkyl-NR¹⁴—(CH₂)₁₋₆—C(═O)NR¹²R¹³, —C₁-C₆-alkyl-NR¹⁴C(═O)—NR¹²R¹³,or —C₁-C₆-alkyl-S(═O)₂NR¹²R¹³; preferably —C₁-C₆-alkyl-(C═O)NR¹²R¹³;wherein in each case said —C₁-C₆-alkyl- is linear or branched, saturatedor unsaturated, unsubstituted or substituted with one, two, three orfour substituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl; morepreferably R⁵ means —CH₂CH₂—C(═O)NR¹²R¹³, —CH₂CH(CH₃)—C(═O)NR¹²R¹³, or—CH₂C(CH₃)₂—C(═O)NR¹²R¹³; and wherein in each case R¹², R¹³ and R¹⁴independently of one another mean

-   -   —H;    -   —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,        unsubstituted or substituted with one, two, three or four        substituents independently of one another selected from the        group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂, and        —O—C₁-C₆-alkyl;    -   a 3-12-membered cycloalkyl moiety, saturated or unsaturated,        unsubstituted; wherein said 3-12-membered cycloalkyl moiety is        optionally connected through —C₁-C₆-alkylene-, linear or        branched, saturated or unsaturated, unsubstituted or substituted        with one, two, three or four substituents independently of one        another selected from the group consisting of —F, —Cl, —Br, —I,        —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl;    -   a 3-12-membered heterocycloalkyl moiety, saturated or        unsaturated, unsubstituted; wherein said 3-12-membered        heterocycloalkyl moiety is optionally connected through        —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,        unsubstituted or substituted with one, two, three or four        substituents independently of one another selected from the        group consisting of —F, —Cl, —Br, —I, —CN, —OH, —NH₂,        —C₁-C₆-alkyl and —O—C₁-C₆-alkyl;    -   a 6-14-membered aryl moiety, unsubstituted, mono- or        polysubstituted; wherein said 6-14-membered aryl moiety is        optionally connected through —C₁-C₆-alkylene-, linear or        branched, saturated or unsaturated, unsubstituted or substituted        with one, two, three or four substituents independently of one        another selected from the group consisting of —F, —Cl, —Br, —I,        —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl; or    -   a 5-14-membered heteroaryl moiety, unsubstituted, mono- or        polysubstituted; wherein said 5-14-membered heteroaryl moiety is        optionally connected through —C₁-C₆-alkylene-, linear or        branched, saturated or unsaturated, unsubstituted or substituted        with one, two, three or four substituents independently of one        another selected from the group consisting of —F, —Cl, —Br, —I,        —CN, —OH, —NH₂, —C₁-C₆-alkyl and —O—C₁-C₆-alkyl;    -   or R¹² and R¹³ within —C(═O)NR¹²R¹³, —OC(═O)NR¹²R¹³, —NR¹²R¹³,        —NR¹⁴—(CH₂)₁₋₆—C(═O)NR¹²R¹³, —NR¹⁴C(═O)—NR¹²R¹³, or        —S(═O)₂NR¹²R¹³ together with the nitrogen atom to which they are        attached form a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or        —(CH₂)₂—NR^(B)—(CH₂)₂—, wherein R^(B) means —H or —C₁-C₆-alkyl,        linear or branched, saturated or unsaturated, unsubstituted or        substituted with one, two, three or four substituents        independently of one another selected from the group consisting        of —F, —Cl, —Br and —I.

In another preferred embodiment of the compound according to theinvention, R⁵ means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, monosubstituted with a 3-12-membered heterocycloalkylmoiety, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; wherein said 3-12-membered heterocycloalkyl moiety isoptionally connected through —C═O—. Preferably, R⁵ means—C₁-C₆-alkyl-(C═O)-3-12-membered heterocycloalkyl, saturated orunsaturated, unsubstituted, mono- or polysubstituted. More preferably,R⁵ means —CH₂—(═O)-oxetanyl, —CH₂—(═O)-tetrahydrofuranyl,—CH₂—(═O)-tetrahydropyranyl, —CH₂—(═O)-oxetanyl,—CH₂—(═O)-tetrahydrofuranyl, —CH₂—(═O)-tetrahydropyranyl,—CH₂—(═O)-piperidinyl, —CH₂—(═O)-piperazinyl, —CH₂—(═O)-morpholinyl,—CH₂—(═O)-thiomorpholinyl, —CH₂—(═O)-1-oxo-thiomorpholinyl, or—CH₂—(═O)-1,1-dioxo-thiomorpholinyl, in each case unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,—OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl,—C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyland —S(═O)₂C₁-C₄-alkyl. Preferably, R⁵ means oxetanyl, optionallymonosubstituted with —F or —OH, and connected through —CH₂— or —CH₂CH₂—.

In another preferred embodiment of the compound according to theinvention, R⁵ means a 3-12-membered cycloalkyl moiety, saturated orunsaturated, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl,—C₁-C₄-alkyl-OH, —O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀—CH₃, —C(═O)OH,—C(═O)C₁-C₄-alkyl,

—C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl,—C(═O)N(C₁-C₄-alkyl)₂, —NH₂, —NHC₁-C₄-alkyl, N(C₁-C₄-alkyl)₂,—NHC(═O)—C₁-C₄-alkyl, —N(C₁-C₄-alkyl)C(═O)C₁-C₄-alkyl, —S(═O)C₁-C₄-alkyland —S(═O)₂C₁-C₄-alkyl; wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted. Preferably, R⁵ meanscyclobutyl, optionally monosubstituted with —F or —OH, and connectedthrough —CH₂—.

In a preferred embodiment of the compound according to the invention, R⁵means a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C₁-C₄-alkyl-OH,—O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀—CH₃, —C(═O)OH, —C(═O)C₁-C₄-alkyl,—C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl,—C(═O)N(C₁-C₄-alkyl)₂, —NH₂, —NHC₁-C₄-alkyl, N(C₁-C₄-alkyl)₂,—NHC(═O)—C₁-C₄-alkyl, —N(C₁-C₄-alkyl)C(═O)C₁-C₄-alkyl, —S(═O)C₁-C₄-alkyland

—S(═O)₂C₁-C₄-alkyl; wherein said 3-12-membered heterocycloalkyl moietyis optionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted. Preferably, R⁵ means -oxetanyl,-tetrahydrofuranyl, -tetrahydropyranyl, -piperidinyl, -piperazinyl,-morpholinyl or -thiomorpholinyl, in each case unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,—OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl,—C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyland —S(═O)₂C₁-C₄-alkyl; wherein said -oxetanyl, -tetrahydrofuranyl,-tetrahydropyranyl, -piperidinyl, -piperazinyl, -morpholinyl or-thiomorpholinyl is connected through —CH₂— or —CH₂CH₂—.

In a preferred embodiment of the compound according to the invention, R⁵means -phenyl, unsubstituted, mono- or polysubstituted; wherein saidphenyl is optionally connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or wherein said phenyl is optionally connected through—C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—. Preferably, R⁵ means-phenyl unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F; —Cl; —Br; —I; —CN; —OH; —C₁-C₄-alkyl; —C(CH₃)₂₀H;—CF₃; -3-12-membered cycloalkyl, saturated or unsaturated,unsubstituted, mono- or polysubstituted; preferably -cyclopropyl,saturated, unsubstituted; -3-12-membered heterocycloalkyl, saturated orunsaturated, unsubstituted, mono- or polysubstituted; preferably

-pyrrolidinyl, -piperidinyl, -morpholinyl, -piperazinyl,-thiomorpholinyl, or -thiomorpholinyl dioxide, in each case saturated,unsubstituted or monosubstituted with —C₁-C₄-alkyl; -6-14-membered aryl,unsubstituted, mono- or polysubstituted; preferably -phenyl,unsubstituted; —O—C₁-C₄-alkyl; —S—C₁-C₄-alkyl; —C(═O)OH;—C(═O)O—C₁-C₄-alkyl; —C(═O)NH₂; —C(═O)NHC₁-C₄-alkyl;—C(═O)N(C₁-C₄-alkyl)₂; —C(═O)N(C₁-C₄-alkyl)(C₁-C₄-alkyl-OH);—C(═O)NH—(CH₂)₁₋₃-3-12-membered cycloalkyl, saturated or unsaturated,unsubstituted or monosubstituted with —OH; preferably—C(═O)NH—(CH₂)₁₋₃-cyclobutyl, saturated or unsaturated, unsubstituted ormonosubstituted with —OH; —C(═O)-3-12-membered heterocycloalkyl,saturated or unsaturated, unsubstituted, mono- or polysubstituted;preferably —C(═O)-morpholinyl, saturated, unsubstituted;—S(═O)C₁-C₄-alkyl; —S(═O)₂C₁-C₄-alkyl; and —S(═O)₂N(C₁-C₄-alkyl)₂; ineach case optionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—,or —S(═O)₂—. Preferably, R⁵ means phenyl or benzyl, in each caseunsubstituted or substituted with one, two, or three substituentsindependently of one another selected from the group consisting of —CH₃,—C(CH₃)₂OH, and -morpholinyl.

In another preferred embodiment of the compound according to theinvention, R⁵ means -1,2-benzodioxole, -pyrazinyl, -pyridazinyl,-pyridinyl, -pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl,-thiazolyl, -1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl,-benzoxazolyl, -pyrazolyl, -quinolinyl, -isoquinolinyl, -quinazolinyl,-indolyl, -indolinyl, -benzo[c][1,2,5]oxadiazolyl,-imidazo[1,2-a]pyrazinyl, or -1H-pyrrolo[2,3-b]pyridinyl, in each caseunsubstituted, mono- or polysubstituted; preferably -pyrazinyl,-pyridazinyl, -pyridinyl, -pyrimidinyl, or -thienyl, in each caseunsubstituted, mono- or polysubstituted; in each case optionallyconnected through —C₁-C₆-alkylene-, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted; or in each caseoptionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or—S(═O)₂—. Preferably, R⁵ means -pyrazinyl, -pyridazinyl, -pyridinyl,-pyrimidinyl, or -thienyl, in each case unsubstituted or substitutedwith one, two, three or four substituents independently of one anotherselected from the group consisting of —F; —Cl; —Br; —I; —CN; —OH;—C₁-C₄-alkyl; —CF₃; -3-12-membered cycloalkyl, saturated or unsaturated,unsubstituted, mono- or polysubstituted; preferably -cyclopropyl,saturated, unsubstituted; -3-12-membered heterocycloalkyl, saturated orunsaturated, unsubstituted, mono- or polysubstituted; preferably-pyrrolidinyl, -piperidinyl, -morpholinyl,

-piperazinyl, -thiomorpholinyl, or -thiomorpholinyl dioxide, in eachcase saturated, unsubstituted or monosubstituted with —C₁-C₄-alkyl;-6-14-membered aryl, unsubstituted, mono- or polysubstituted; preferably-phenyl, unsubstituted; —O—C₁-C₄-alkyl; —S—C₁-C₄-alkyl; —C(═O)OH;—C(═O)O—C₁-C₄-alkyl; —C(═O)NH₂; —C(═O)NHC₁-C₄-alkyl;—C(═O)N(C₁-C₄-alkyl)₂; —C(═O)N(C₁-C₄-alkyl)(C₁-C₄-alkyl-OH);—C(═O)NH—(CH₂)₁₋₃-3-12-membered cycloalkyl, saturated or unsaturated,unsubstituted or monosubstituted with —OH; preferably—C(═O)NH—(CH₂)₁₋₃-cyclobutyl, saturated or unsaturated, unsubstituted ormonosubstituted with —OH; —C(═O)-3-12-membered heterocycloalkyl,saturated or unsaturated, unsubstituted, mono- or polysubstituted;preferably —C(═O)-morpholinyl, saturated, unsubstituted;—S(═O)C₁-C₄-alkyl; —S(═O)₂C₁-C₄-alkyl; and —S(═O)₂N(C₁-C₄-alkyl)₂.Preferably, R⁵ means -pyridinyl, —CH₂-pyridinyl, or -pyrimidinyl, ineach case unsubstituted or substituted with one, two, or threesubstituents independently of one another selected from the groupconsisting of —CN, —CH₃, —CHF₂, —C(CH₃)₂OH, —OCH₃, —OCF₃, -cyclopropyl,-morpholinyl, -azetanyl, and -pyridyl.

In still another preferred embodiment of the compound according to theinvention, R⁵ means a bicyclic 9-10-membered heteroaryl moiety,unsubstituted, mono- or polysubstituted. Preferably, R⁵ meansimidazo[1,2-a]pyrazine, unsubstituted or monosubstituted with—C₁-C₄-alkyl.

In a particularly preferred embodiment of the compound according to theinvention

R¹ means —H or —CH₃;R² means —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted;-cyclopropyl; or -cyclopropylmethylene;or R¹ and R² together with the nitrogen atom to which they are attachedform a ring and mean -azetidine or -pyrrolidine;R³ means -phenyl, -thienyl or -pyridinyl, in each case unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —CN,—C₁-C₄-alkyl, —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —OCF₃, —OH,—O—C₁-C₄-alkyl, —OCH₃, —C(═O)NH₂, C(═O)NHCH₃, —C(═O)N(CH₃)₂, —NH₂,—NHCH₃, —N(CH₃)₂, —NHC(═O)CH₃, —CH₂OH, SOCH₃ and SO₂CH₃; orR⁴ means

-   -   —H;    -   —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted or        substituted with one, two, three or four substituents        independently of one another selected from the group consisting        of —F, —Cl, —Br, —I, —CN, —OH, ═O, —S(═O)₂—C₁-C₄-alkyl and        —O—C₁-C₄-alkyl;    -   3-6-membered cycloalkyl, unsubstituted or substituted with one,        two, three or four substituents independently of one another        selected from the group consisting of —F, —Cl, —Br, —I, —CN,        —OH, and —O—C₁-C₄-alkyl, wherein said 3-6-membered cycloalkyl is        connected through —C₁-C₆-alkylene;    -   3-12-membered heterocycloalkyl, saturated or unsaturated,        unsubstituted or substituted with one, two, three or four        substituents independently of one another selected from the        group consisting of —F, —Cl, —Br, —I, —CN, —OH, and        —O—C₁-C₄-alkyl; wherein said 3-12-membered heterocycloalkyl is        optionally connected through —C₁-C₆-alkylene-, unsubstituted or        substituted with ═O;    -   6-14-membered aryl, unsubstituted or substituted with one, two,        three or four substituents independently of one another selected        from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, and        —O—C₁-C₄-alkyl; wherein said 6-14-membered aryl is optionally        connected through —C₁-C₆-alkylene- or —S(═O)₂—;        R⁵ means    -   —H;    -   —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,        unsubstituted or substituted with one, two, three or four        substituents independently of one another selected from the        group consisting of —F, —Cl, —Br, —I, —CN, ═O, —OH,        —O—C₁-C₄-alkyl, —O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀—CH₃,        —C(═O)OH, —C(═O)C₁-C₄-alkyl, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂,        —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂,        —(C═O)-heterocycloalkyl, —S(═O)C₁-C₄-alkyl, —S(═O)₂C₁-C₄-alkyl,        —NH₂, —NH—C₁-C₄-alkyl, —N(C₁-C₄-alkyl)₂, —NHC(═O)—C₁-C₄-alkyl,        —NH—S(═O)₂C₁-C₄-alkyl; preferably —C₁-C₆-alkyl, linear or        branched, saturated or unsaturated, monosubstituted with a        3-12-membered heterocycloalkyl moiety, saturated or unsaturated,        unsubstituted, mono- or polysubstituted; wherein said        3-12-membered heterocycloalkyl moiety is optionally connected        through —C═O—;    -   3-12-membered heterocycloalkyl, saturated or unsaturated,        unsubstituted or substituted with one, two, three or four        substituents independently of one another selected from the        group consisting of —F, —Cl, —Br, —I, —CN, ═O, —OH,        —C₁-C₄-alkyl, —NH₂, —NH—C₁-C₄-alkyl, —N(C₁-C₄-alkyl)₂,        —NHC(═O)—C₁-C₄-alkyl, —NHS(═O)₂—C₁-C₄-alkyl, —O—C₁-C₄-alkyl,        —O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀—CH₃, —C(═O)OH,        —C(═O)OC₁-C₄-alkyl, —C(═O)C₁-C₄-alkyl, —C(═O)NH₂,        —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl,        —S(═O)₂C₁-C₄-alkyl, -phenyl, —C(═O)-phenyl, —C(═O)-pyridyl,        -pyridyl, -pyrimidinyl, and -pyridazinyl; wherein said        3-12-membered heterocycloalkyl moiety is optionally connected        through —C₁-C₆-alkylene-, linear or branched, saturated or        unsaturated, unsubstituted; or wherein said 3-12-membered        heterocycloalkyl moiety is optionally connected through —C═O— or        —CH₂—C═O—;    -   1,2-benzodioxole, -pyrazinyl, -pyridazinyl, -pyridinyl,        -pyrimidinyl, -thienyl, -imidazolyl, -benzimidazolyl,        -thiazolyl, -1,3,4-thiadiazolyl, -benzothiazolyl, -oxazolyl,        -benzoxazolyl, -pyrazolyl, -quinolinyl, -isoquinolinyl,        -quinazolinyl, -indolyl, -indolinyl,        -benzo[c][1,2,5]oxadiazolyl, -imidazo[1,2-a]pyrazinyl, or        -1H-pyrrolo[2,3-b]pyridinyl, in each case unsubstituted, mono-        or polysubstituted;    -   and        R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ mean —H; or R⁶ and R⁷ together mean        ═O and R⁸, R⁹, R¹⁰, and R¹¹ mean —H.

In preferred embodiments, the compound according to the invention has astructure according to any of general formulas (II-A) to (VI-F):

wherein in each caseR¹, R², R³, R⁴, and R⁵ are defined as above,R^(C) means —H, —OH, —F, —CN or —C₁-C₄-alkyl; preferably —H or —OH;R^(D) means —H or —F;or a physiologically acceptable salt thereof.

In preferred embodiments, the compound according to the invention,preferably the compound according to any of general formulas (II-A) to(VI-F), has a structure wherein R⁵ means

—CR^(I)R^(J)—CR^(G)R^(H)—C(═O)—X—R^(E)

whereinX means —O—, —S— or —NR^(F)—;R^(E) means

-   -   —H;    -   —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,        unsubstituted, mono- or polysubstituted;    -   a 3-12-membered cycloalkyl moiety, saturated or unsaturated,        unsubstituted, mono- or polysubstituted; wherein said        3-12-membered cycloalkyl moiety is optionally connected through        —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,        unsubstituted, mono- or polysubstituted;    -   a 3-12-membered heterocycloalkyl moiety, saturated or        unsaturated, unsubstituted, mono- or polysubstituted; wherein        said 3-12-membered heterocycloalkyl moiety is optionally        connected through —C₁-C₆-alkylene-, linear or branched,        saturated or unsaturated, unsubstituted, mono- or        polysubstituted;    -   a 6-14-membered aryl moiety, unsubstituted, mono- or        polysubstituted; wherein said 6-14-membered aryl moiety is        optionally connected through —C₁-C₆-alkylene-, linear or        branched, saturated or unsaturated, unsubstituted, mono- or        polysubstituted; or    -   a 5-14-membered heteroaryl moiety, unsubstituted, mono- or        polysubstituted; wherein said 5-14-membered heteroaryl moiety is        optionally connected through —C₁-C₆-alkylene-, linear or        branched, saturated or unsaturated, unsubstituted, mono- or        polysubstituted;        in case X means NR^(F), R^(F) means    -   —H;    -   —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,        unsubstituted, mono- or polysubstituted;    -   a 3-12-membered cycloalkyl moiety, saturated or unsaturated,        unsubstituted, mono- or polysubstituted; wherein said        3-12-membered cycloalkyl moiety is optionally connected through        —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,        unsubstituted, mono- or polysubstituted;    -   a 3-12-membered heterocycloalkyl moiety, saturated or        unsaturated, unsubstituted, mono- or polysubstituted; wherein        said 3-12-membered heterocycloalkyl moiety is optionally        connected through —C₁-C₆-alkylene-, linear or branched,        saturated or unsaturated, unsubstituted, mono- or        polysubstituted;    -   a 6-14-membered aryl moiety, unsubstituted, mono- or        polysubstituted; wherein said 6-14-membered aryl moiety is        optionally connected through —C₁-C₆-alkylene-, linear or        branched, saturated or unsaturated, unsubstituted, mono- or        polysubstituted; or    -   a 5-14-membered heteroaryl moiety, unsubstituted, mono- or        polysubstituted; wherein said 5-14-membered heteroaryl moiety is        optionally connected through —C₁-C₆-alkylene-, linear or        branched, saturated or unsaturated, unsubstituted, mono- or        polysubstituted;        or in case X means NR^(F), R^(E) and R^(F) together with the        nitrogen atom to which they are attached form a 3-12-membered        heterocycloalkyl moiety, saturated or unsaturated,        unsubstituted, mono- or polysubstituted;        R^(G), R^(H), R^(I), R^(J), independently of one another mean        —H, —F, —Cl, —Br, —I, —OH, or —C₁-C₆-alkyl, linear or branched,        saturated or unsaturated, unsubstituted, mono- or        polysubstituted;        or R^(G) and R^(H) together with the carbon atom to which they        are attached form a 3-12-membered cycloalkyl moiety, saturated        or unsaturated, unsubstituted, mono- or polysubstituted; or a        3-12-membered heterocycloalkyl moiety, saturated or unsaturated,        unsubstituted, mono- or polysubstituted;

In preferred embodiments,

R^(G) and R^(H) independently of one another mean —H or —C₁-C₆-alkyl;preferably —H or —CH₃; or R^(G) and R^(H) together with the carbon atomto which they are attached form a 3-12-membered cycloalkyl moiety,saturated or unsaturated, unsubstituted, mono- or polysubstituted;preferably cyclopropyl, cyclobutyl or cyclopentyl, in each caseunsubstituted; or a 3-12-membered heterocycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted; preferablyoxetanly, tetrahydrofuranyl or tetrahydropyranyl, in each caseunsubstituted; and/orR^(I), R^(J), independently of one another mean —H, —F, —OH, or—C₁-C₆-alkyl; preferably —H.

In a preferred embodiment, R^(E) means —H.

In another preferred embodiment, R^(E) means —C₁-C₆-alkyl, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted. Preferably, R^(E) means —C₁-C₆-alkyl, linear orbranched, saturated, unsubstituted, mono- or polysubstituted. Morepreferably, R^(E) means —C₁-C₆-alkyl, linear or branched, saturated,unsubstituted or monosubstituted with a substituent selected from thegroup consisting of —F, —Cl, —Br, —I, —CN, —OH, —O—C₁-C₄-alkyl,—C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl,—C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl.

In still another preferred embodiment, R^(E) means a 3-12-memberedcycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- orpolysubstituted, wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted;preferably through —CH₂— or —CH₂CH₂—. Preferably, R^(E) means a3-6-membered cycloalkyl moiety, saturated, unsubstituted, mono- orpolysubstituted, wherein said 3-12-membered cycloalkyl moiety isconnected through —C₁-C₆-alkylene-, linear or branched, saturated,unsubstituted. More preferably, R^(E) means -cyclobutyl, unsubstitutedor monosubstituted with —F, —OH, —CN or —C₁-C₄-alkyl, wherein said-cyclobutyl is connected through —CH₂— or —CH₂CH₂—.

In yet another preferred embodiment, R^(E) means a 3-12-memberedheterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-or polysubstituted; wherein said 3-12-membered heterocycloalkyl moietyis optionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted.Preferably, R^(E) means a 4-6-membered heterocycloalkyl moiety,saturated or unsaturated, unsubstituted, mono- or polysubstituted. Morepreferably, R^(E) means -heterocyclobutyl, unsubstituted.

In a further preferred embodiment, R^(E) means a 5-14-memberedheteroaryl moiety, unsubstituted, mono- or polysubstituted; wherein said5-14-membered heteroaryl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted. Preferably, R^(E) means a5-6-membered heteroaryl moiety, unsubstituted, mono- or polysubstituted,wherein said 5-6-membered heteroaryl moiety is optionally connectedthrough —CH₂—. More preferably, R^(E) means a 5-6-membered heteroarylmoiety, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl,—C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl,—C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl, whereinsaid 5-6-membered heteroaryl moiety is optionally connected through—CH₂—. Still more preferably, R^(E) means -oxazolyl, -pyridinyl,-pyridazinyl or -pyrimidinyl, in each case unsubstituted or substitutedwith one, two, three or four substituents independently of one anotherselected from the group consisting of —F, —Cl, Br, —I, —CN, —OH,—C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂,—C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, S(═O)C₁-C₄-alkyl and—S(═O)₂C₁-C₄-alkyl, wherein said -oxazolyl, -pyridinyl, -pyridazinyl or-pyrimidinyl is optionally connected through —CH₂—.

In a preferred embodiment, X means NR^(F) and R^(E) and R^(F) togetherwith the nitrogen atom to which they are attached form a 3-12-memberedheterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-or polysubstituted. Preferably, X means NR^(F) and R^(E) and R^(F)together with the nitrogen atom to which they are attached form a5-6-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted. More preferably, X means NR^(F)and R^(E) and R^(F) together with the nitrogen atom to which they areattached form -pyrrolidinyl, -pyrimidinyl, -morpholinyl,-thiomorpholinyl, -thiomorpholinyl dioxide, or -piperazinyl, in eachcase unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of ═O, —OH, and —C(═O)NH₂, wherein said -pyrrolidinyl,-pyrimidinyl, -morpholinyl, -thiomorpholinyl, -thiomorpholinyl dioxide,or -piperazinyl is optionally condensed with an imidazole moiety,unsubstituted.

In a preferred embodiment, R^(E) means

-   -   —H;    -   —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,        unsubstituted or substituted with one, two, three or four        substituents independently of one another selected from the        group consisting of —F, —Cl, —Br, —I, —CN, —O—C₁-C₄-alkyl,        —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl,        —C(═O)N(C₁-C₄-alkyl)₂, —OH, —S(═O)C₁-C₄-alkyl and        —S(═O)₂C₁-C₄-alkyl;    -   -cyclobutyl, unsubstituted or monosubstituted with —OH; wherein        said -cyclobutyl is connected through —CH₂—;    -   -heterocyclobutyl, unsubstituted; or    -   -oxazolyl, -pyridinyl, -pyridazinyl or -pyrimidinyl, in each        case unsubstituted or substituted with one, two, three or four        substituents independently of one another selected from the        group consisting of —F, —Cl, Br, —I, —OH, —O—C₁-C₄-alkyl, —CN,        and —S(═O)₂C₁-C₄-alkyl; wherein said -oxazolyl, -pyridinyl,        -pyridazinyl or -pyrimidinyl is optionally connected through        —CH₂—;        in case X means NR^(F), R^(F) means —H or —CH₃;        or in case X means NR^(F), R^(E) and R^(F) together with the        nitrogen atom to which they are attached form a piperidine        moiety, a pyrrolidine moiety, a morpholine moiety, a        thiomorpholine moiety, a thiomorpholine dioxide moiety, or a        piperazine moiety, in each case unsubstituted or substituted        with one, two, three or four substituents independently of one        another selected from the group consisting of ═O, —OH, and        —C(═O)NH₂; wherein said piperidine moiety, pyrrolidine moiety,        morpholine moiety, thiomorpholine moiety, thiomorpholine dioxide        moiety, or piperazine moiety is optionally condensed with an        imidazole moiety, unsubstituted.

In a preferred embodiment, X means NR^(F) and R^(F) means —H or—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted. Preferably, R^(F) means —H or—CH₃. More preferably, R^(F) means —H.

Preferably, R⁵ has a meaning selected from the group consisting of:

Preferred compounds according to the invention are selected from thegroup consisting of:

-   2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetamide-   2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro-[3.4]-octan-6-one-   5-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)-4-methoxypyrimidine-2-carbonitrile-   5-(cyclobutylmethyl)-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one-   2-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3,4]octan-7-yl)acetamide-   5-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)-4-methoxypyrimidine-2-carbonitrile-   2-(dimethylamino)-7-(4-methyl-2-morpholin-4-ylpyrimidin-5-yl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one-   7-(6-(azetidin-1-yl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one-   5-(2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methyl-picolinonitrile-   5-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methyl-picolinonitrile-   6-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-5-methyl-nicotinonitrile-   2-(dimethylamino)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]-octan-6-one-   5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one-   2-(dimethylamino)-7-(4-methyl-6-morpholinopyridin-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one-   2-(dimethylamino)-7-(6-(2-hydroxypropan-2-yl)-4-methylpyridin-3-yl)-2-phenyl-5,7-diazaspiro-[3.4]octan-6-one-   2-(dimethylamino)-7-(4-(2-hydroxypropan-2-yl)-2-methylphenyl)    -2-phenyl-5,7-diazaspiro[3.4]-octan-6-one-   7-(6-(difluoromethyl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro-[3.4]octan-6-one-   2-(dimethylamino)-5-((3-fluorooxetan-3-yl)methyl)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)-pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one-   5-(cyclopropylmethyl)-7-(6-(difluoromethyl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-(3-fluoro-phenyl)-5,7-diazaspiro[3.4]octan-6-one-   2-(dimethylamino)-7-(2-morpholinopyrimidin-5-yl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one-   2-(dimethylamino)-5-((1-fluorocyclopropyl)methyl)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)-pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one-   2-(dimethylamino)-2-(3-fluorophenyl)-5-((1-hydroxycyclobutyl)methyl)-7-(5-(trifluoromethoxy)-pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one-   5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-(2-hydroxypropan-2-yl)phenyl)-5,7-diazaspiro[3.4]octan-6-one-   2-(dimethylamino)-5-((3-fluorooxetan-3-yl)methyl)-2-phenyl-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one-   5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,7-diazaspiro[3.4]octan-6-one-   5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(2-(methylsulfonyl)ethyl)-5,7-diazaspiro[3.4]octan-6-one-   5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one-   5-(cyclopropylmethyl)-2-(dimethylamino)-7-((3-fluorooxetan-3-yl)methyl)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one-   5-(cyclopropylmethyl)-7-(6-cyclopropylpyridin-3-yl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro-[3.4]octan-6-one-   7-(6-cyclopropyl-4-methylpyridin-3-yl)-5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one-   7-(6-cyclopropyl-4-methylpyridin-3-yl)-2-(dimethylamino)-5-((3-fluorooxetan-3-yl)methyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one-   5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(2-methoxy-2-methylpropyl)-5,7-diazaspiro[3.4]octan-6-one-   2-(dimethylamino)-2-phenyl-7-(2-pyridin-4-ylpyrimidin-5-yl)-5,7-diazaspiro[3.4]octan-6-one-   5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-7-[5-(trifluoromethyl)pyridin-3-yl]-5,7-diazaspiro[3.4]octan-6-one-   5-[5-(cyclopropylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile-   2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-morpholinobenzyl)-5,7-diazaspiro[3.4]octan-6-one-   5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-[(1-hydroxycyclobutyl)methyl]-5,7-diazaspiro[3.4]octan-6-one-   5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-7-(2-pyridin-4-ylpyrimidin-5-yl)-5,7-diaza-spiro[3.4]octan-6-one-   3-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)propanenitrile-   3-[5-(cyclopropylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl]-propanenitrile-   5-(cyclopropylmethyl)-2-(dimethylamino)-7-[(1-hydroxycyclobutyl)methyl]-2-phenyl-5,7-diaza-spiro[3.4]octan-6-one-   5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-[2-(oxetan-3-yl)ethyl]-5,7-diaza-spiro[3.4]octan-6-one    and the physiologically acceptable salts thereof.

According to the invention, unless expressly stated otherwise,“—C₁-C₄-alkyl”, “—C₁-C₆-alkyl” and any other alkyl residues can belinear or branched, saturated or unsaturated. Linear saturated alkylincludes methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl.Examples of branched saturated alkyl include but are not limited toiso-propyl, sec-butyl, and tert-butyl. Examples of linear unsaturatedalkyl include but are not limited to vinyl, propenyl, allyl, andpropargyl.

According to the invention, unless expressly stated otherwise,“—C₁-C₄-alkyl”, “—C₁-C₆-alkyl” and any other alkyl residues can beunsubstituted, mono- or polysubstituted. Examples of substituted alkylinclude but are not limited to —CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃,—CH₂CH₂S(═O)₂CH₃, —CH₂C(═O)NH₂, —C(CH₃)₂C(═O)NH₂, —CH₂C(CH₃)₂C(═O)NH₂,and —CH₂CH₂C(═O)N(CH₃)₂.

According to the invention, unless expressly stated otherwise,“—C₁-C₆-alkylene-”, “—C₁-C₄-alkylene” and any other alkylene residue canbe unsubstituted, mono- or polysubstituted. Examples of saturatedalkylene include but are not limited to —CH₂—, —CH(CH₃)—, —C(CH₃)₂—,—CH₂CH₂—, —CH(CH₃)CH₂—, —CH₂CH(CH₃)—, —CH(CH₃)—CH(CH₃)—, —C(CH₃)₂CH₂—,—CH₂C(CH₃)₂—, —CH(CH₃)C(CH₃)₂—, —C(CH₃)₂CH(CH₃)—, C(CH₃)₂C(CH₃)₂—,—CH₂CH₂CH₂—, and —C(CH₃)₂CH₂CH₂—. Examples of unsaturated alkyleneinclude but are not limited to —CH═CH—, —C≡C—, —C(CH₃)═CH—, —CH═C(CH₃)—,—C(CH₃)═C(CH₃)—, —CH₂CH═CH—, —CH═CHCH₂—, —CH═CH—CH═CH—, and —CH═CH—C≡C—.

According to the invention, unless expressly stated otherwise,“—C₁-C₆-alkylene-”, “—C₁-C₄-alkylene” and any other alkylene residue canbe unsubstituted, mono- or polysubstituted. Examples of substituted—C₁-C₆-alkylene-include but are not limited to —CHF—, —CF₂—, —CHOH— and—C(═O)—.

According to the invention, moieties may be connected through—C₁-C₆-alkylene-, i.e. the moieties may not be directly bound to thecore structure of compound according to general formula (I), but may beconnected to the core structure of compound according to general formula(I) or its periphery through a —C₁-C₆-alkylene-linker.

According to the invention, “3-12-membered cycloalkyl moiety” means anon-aromatic, monocyclic, bicyclic or tricyclic moiety comprising 3 to12 ring carbon atoms but no heteroatoms in the ring. Examples ofpreferred saturated 3-12-membered cycloalkyl moieties according to theinvention include but are not limited to cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane, hydrindane, anddecaline. Examples of preferred unsaturated 3-12-membered cycloalkylmoiety moieties according to the invention include but are not limitedto cyclopropene, cyclobutene, cyclopentene, cyclopentadiene,cyclohexene, 1,3-cyclohexadiene, and 1,4-cyclohexadiene. The3-12-membered cycloalkyl moiety, which is bonded to the compoundaccording to the invention, in its periphery may optionally be condensedwith a 3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; and/or with a 6-14-memberedaryl moiety, unsubstituted, mono- or polysubstituted; and/or with a5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted. Under these circumstances, the ring atoms of thecondensed moieties are not included in the 3 to 12 ring atoms of the3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkylmoieties condensed with 3-12-membered heterocycloalkyl moieties includebut are not limited to octahydro-1H-indol, decahydroquinoline,decahydroisoquinoline, octahydro-2H-benzo[b][1,4]oxazin, anddecahydroquinoxalin, which in each case are connected through the3-12-membered cycloalkyl moiety. Examples of 3-12-membered cycloalkylmoieties condensed with 6-14-membered aryl moieties include but are notlimited to 2,3-dihydro-1H-indene and tetraline, which in each case areconnected through the 3-12-membered cycloalkyl moiety. Examples of3-12-membered cycloalkyl moieties condensed with 5-14-memberedheteroaryl moieties include but are not limited to5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which ineach case are connected through the 3-12-membered cycloalkyl moiety.

According to the invention, the 3-12-membered cycloalkyl moiety mayoptionally be connected through —C₁-C₆-alkylene-, i.e. the 3-12-memberedcycloalkyl moiety may not be directly bound to the compound according togeneral formula (I) but may be connected thereto through a—C₁-C₆-alkylene-linker. Examples include but are not limited to—CH₂-cyclopropyl, —CH₂-cyclobutyl, —CH₂-cyclopentyl, —CH₂-cyclohexyl,—CH₂CH₂-cyclopropyl, —CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclopentyl, and—CH₂CH₂-cyclohexyl.

According to the invention, unless expressly stated otherwise, the3-12-membered cycloalkyl moiety can be unsubstituted, mono- orpolysubstituted. Examples of substituted 3-12-membered cycloalkylmoieties include but are not limited to —CH₂-1-hydroxy-cyclobutyl.

According to the invention, “3-12-membered heterocycloalkyl moiety”means a non-aromatic, monocyclic, bicyclic or tricyclic moietycomprising 3 to 12 ring atoms, wherein each cycle comprisesindependently of one another 1, 2, 3, 4 or more heteroatomsindependently of one another selected from the group consisting ofnitrogen, oxygen and sulfur, whereas sulfur may be oxidized (S(═O) or(S(═O)₂), whereas the remaining ring atoms are carbon atoms, and whereasbicyclic or tricyclic systems may share common heteroatom(s). Examplesof preferred saturated 3-12-membered heterocycloalkyl moieties accordingto the invention include but are not limited to aziridin, azetidine,pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine,triazolidine, tetrazolidine, oxiran, oxetane, tetrahydrofurane,tetrahydropyrane, thiirane, thietane, tetrahydrothiophene, diazepane,oxazolidine, isoxazolidine, thiazolidine, isothiazolidine,thiadiazolidine, morpholine, thiomorpholine. Examples of preferredunsaturated 3-12-membered heterocycloalkyl moiety moieties according tothe invention include but are not limited to oxazoline, pyrazoline,imidazoline, isoxazoline, thiazoline, isothiazoline, and dihydropyran.The 3-12-membered heterocycloalkyl moiety, which is bonded to thecompound according to the invention, in its periphery may optionally becondensed with a 3-12-membered cycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted; and/or with a6-14-membered aryl moiety, unsubstituted, mono- or polysubstituted;and/or with a 5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted. Under these circumstances, the ring atoms of thecondensed moieties are not included in the 3 to 12 ring atoms of the3-12-membered heterocycloalkyl moieties. Examples of 3-12-memberedheterocycloalkyl moieties condensed with 3-12-membered cycloalkylmoieties include but are not limited to octahydro-1H-indol,decahydroquinoline, decahydroisoquinoline,octahydro-2H-benzo[b][1,4]-oxazin, and decahydroquinoxalin, which ineach case are connected through the 3-12-membered heterocycloalkylmoiety. An examples of a 3-12-membered heterocycloalkyl moiety condensedwith a 6-14-membered aryl moiety includes but is not limited to1,2,3,4-tetrahydroquinoline, which is connected through the3-12-membered heterocycloalkyl moiety. An example of a 3-12-memberedheterocycloalkyl moiety condensed with a 5-14-membered heteroarylmoieties includes but is not limited to5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connectedthrough the 3-12-membered heterocycloalkyl moiety.

According to the invention, the 3-12-membered heterocycloalkyl moietymay optionally be connected through —C₁-C₆-alkylene-, i.e. the3-12-membered heterocycloalkyl moiety may not be directly bound to thecompound according to general formula (I) but may be connected theretothrough a —C₁-C₆-alkylene-linker. Said linker may be connected to acarbon ring atom or to a hetero ring atom of the 3-12-memberedheterocycloalkyl moiety. Examples include but are not limited to—CH₂-oxetane, —CH₂-pyrrolidine, —CH₂-piperidine, —CH₂-morpholine,—CH₂CH₂-oxetane, —CH₂CH₂-pyrrolidine, —CH₂CH₂-piperidine, and—CH₂CH₂-morpholine.

According to the invention, unless expressly stated otherwise, the3-12-membered heterocycloalkyl moiety can be unsubstituted, mono- orpolysubstituted. Examples of substituted 3-12-membered heterocycloalkylmoieties include but are not limited to 2-carboxamido-N-pyrrolidinyl-,3,4-dihydroxy-N-pyrrolidinyl, 3-hydroxy-N-pyrimidinyl,3,4-dihydroxy-N-pyrimidinyl, 3-oxo-N-piperazinyl,-tetrahydro-2H-thiopyranyl dioxide and thiomorpholinyl dioxide.

According to the invention, “6-14-membered aryl moiety” means anaromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14ring carbon atoms but no heteroatoms in the ring. Examples of preferred6-14-membered aryl moieties according to the invention include but arenot limited to benzene, naphthalene, anthracen, and phenanthren. The6-14-membered aryl moiety, which is bonded to the compound according tothe invention, in its periphery may optionally be condensed with a3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; and/or with a 3-12-memberedheterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-or polysubstituted; and/or with a 5-14-membered heteroaryl moiety,unsubstituted, mono- or polysubstituted. Under these circumstances, thering atoms of the condensed moieties are not included in the 6 to 14ring carbon atoms of the 6-14-membered heterocycloalkyl moieties.Examples of 6-14-membered aryl moieties condensed with 3-12-memberedcycloalkyl moieties include but are not limited to 2,3-dihydro-1H-indeneand tetraline, which in each case are connected through the6-14-membered aryl moiety. An example of a 6-14-membered aryl moietycondensed with a 3-12-membered heterocycloalkyl moiety includes but isnot limited to 1,2,3,4-tetrahydroquinoline, which is connected throughthe 6-14-membered aryl moiety. Examples of 6-14-membered aryl moietiescondensed with 5-14-membered heteroaryl moieties include but are notlimited to quinoline, isoquinoline, phenazine and phenoxacine, which ineach case are connected through the 6-14-membered aryl moiety.

According to the invention, the 6-14-membered aryl moiety may optionallybe connected through —C₁-C₆-alkylene-, i.e. the 6-14-membered arylmoiety may not be directly bound to the compound according to generalformula (I) but may be connected thereto through a—C₁-C₆-alkylene-linker. Said linker may be connected to a carbon ringatom or to a hetero ring atom of the 6-14-membered aryl moiety. Examplesinclude but are not limited to —CH₂—C₆H₅, —CH₂CH₂—C₆H₅ and —CH═CH—C₆H₅.

According to the invention, unless expressly stated otherwise, the6-14-membered aryl moiety can be unsubstituted, mono- orpolysubstituted. Examples of substituted 6-14-membered aryl moietiesinclude but are not limited to 2-fluorophenyl, 3-fluorophenyl,2-methoxyphenyl and 3-methoxyphenyl.

According to the invention, “5-14-membered heteroaryl moiety” means anaromatic, monocyclic, bicyclic or tricyclic moiety comprising 6 to 14ring atoms, wherein each cycle comprises independently of one another 1,2, 3, 4 or more heteroatoms independently of one another selected fromthe group consisting of nitrogen, oxygen and sulfur, whereas theremaining ring atoms are carbon atoms, and whereas bicyclic or tricyclicsystems may share common heteroatom(s). Examples of preferred5-14-membered heteroaryl moieties according to the invention include butare not limited to pyrrole, pyrazole, imidazole, triazole, tetrazole,furane, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyridine,pyridazine, pyrimidine, pyrazine, indolicine, 9H-chinolicine,1,8-naphthyridine, purine, imidazo[1,2-a]pyrazine, and pteridine. The5-14-membered heteroaryl moiety, which is bonded to the compoundaccording to the invention, in its periphery may optionally be condensedwith a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; and/or with a 3-12-memberedheterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-or polysubstituted; and/or with a 6-14-membered aryl moiety,unsubstituted, mono- or polysubstituted. Under these circumstances, thering atoms of the condensed moieties are not included in the 6 to 14ring carbon atoms of the 6-14-membered heterocycloalkyl moieties.Examples of 5-14-membered heteroaryl moieties condensed with3-12-membered cycloalkyl moieties include but are not limited to5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroquinazoline, which ineach case are connected through the 5-14-membered heteroaryl moiety. Anexamples of a 5-14-membered heteroaryl moiety condensed with a3-12-membered heterocycloalkyl moiety includes but is not limited to5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine, which is connectedthrough the 5-14-membered heteroaryl moiety. Examples of 5-14-memberedheteroaryl moieties condensed with 6-14-membered aryl moieties includebut are not limited to quinoline, isoquinoline, phenazine andphenoxacine, which in each case are connected through the 5-14-memberedheteroaryl moiety.

According to the invention, the 5-14-membered heteroaryl moiety mayoptionally be connected through —C₁-C₆-alkylene-, i.e. the 5-14-memberedheteroaryl moiety may not be directly bound to the compound according togeneral formula (I) but may be connected thereto through a—C₁-C₆-alkylene-linker. Said linker may be connected to a carbon ringatom or to a hetero ring atom of the 5-14-membered heteroaryl moiety.Examples include but are not limited to —CH₂-oxazole, —CH₂-isoxazole,—CH₂-imidazole, —CH₂-pyridine, —CH₂-pyrimidine, —CH₂-pyridazine,—CH₂CH₂-oxazole, —CH₂CH₂-isoxazole, —CH₂CH₂-imidazole, —CH₂CH₂-pyridine,—CH₂CH₂-pyrimidine, and —CH₂CH₂-pyridazine.

According to the invention, unless expressly stated otherwise, the5-14-membered heteroaryl moiety can be unsubstituted, mono- orpolysubstituted. Examples of 5-14-membered heteroaryl moieties includebut are not limited to 2-methoxy-4-pyridinyl, 2-methoxy-5-pyridinyl,3-methoxy-4-pyridinyl, 3-methoxy-6-pyridinyl, 4-methoxy-2-pyridinyl,2-methylsulfonyl-5-pyridinyl, 3-methylsulfonyl-6-pyridinyl,3-methoxy-6-pyridazinyl, 2-nitrilo-5-pyrimidinyl,4-hydroxy-2-pyrimidinyl, 4-methoxy-pyrimidinyl,4-methoxy-pyrimidinyl-2-carbonitrile, and 2-methoxy-6-pyrazinyl.

Preferably, the compounds according to the invention have a structureaccording to general formula (I′) or (I″)

wherein R¹ to R¹¹ are defined as above, or a physiologically acceptablesalt thereof

In one preferred embodiment, the excess of the cis-isomer so designatedis at least 50% de, more preferably at least 75% de, yet more preferablyat least 90% de, most preferably at least 95% de and in particular atleast 99% de.

Preferred compounds according to the invention are selected from thegroup consisting of:

-   cis-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetamide-   cis-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro-[3.4]octan-6-one-   cis-5-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)-4-methoxypyrimidine-2-carbonitrile-   trans-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro-[3.4]octan-6-one-   trans-5-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)-4-methoxypyrimidine-2-carbonitrile-   cis-5-(cyclobutylmethyl)-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one-   trans-5-(cyclobutylmethyl)-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one-   cis-2-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl-)acetamide-   trans-2-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)-acetamide-   cis-5-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)-4-methoxypyrimidine-2-carbonitrile-   trans-5-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)-4-methoxypyrimidine-2-carbonitrile-   cis-2-(dimethylamino)-7-(4-methyl-2-morpholin-4-ylpyrimidin-5-yl)-2-phenyl-5,7-diazaspiro-[3.4]octan-6-one-   cis-7-(6-(azetidin-1-yl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one-   cis-5-(2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methyl-picolinonitrile-   cis-5-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methylpicolinonitrile-   cis-6-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-5-methylnicotinonitrile-   cis-2-(dimethylamino)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]-octan-6-one-   cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one-   cis-2-(dimethylamino)-7-(4-methyl-6-morpholinopyridin-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one-   cis-2-(dimethylamino)-7-(6-(2-hydroxypropan-2-yl)-4-methylpyridin-3-yl)-2-phenyl-5,7-diazaspiro-[3.4]octan-6-one-   cis-2-(dimethylamino)-7-(4-(2-hydroxypropan-2-yl)-2-methylphenyl)-2-phenyl-5,7-diazaspiro-[3.4]octan-6-one-   cis-7-(6-(difluoromethyl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diaza-spiro[3.4]octan-6-one-   cis-2-(dimethylamino)-5-((3-fluorooxetan-3-yl)methyl)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)-pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one-   cis-5-(cyclopropylmethyl)-7-(6-(difluoromethyl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one-   cis-2-(dimethylamino)-7-(2-morpholinopyrimidin-5-yl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one-   cis-2-(dimethylamino)-5-((1-fluorocyclopropyl)methyl)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)-pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one-   cis-2-(dimethylamino)-2-(3-fluorophenyl)-5-((1-hydroxycyclobutyl)methyl)-7-(5-(trifluoromethoxy)-pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one-   cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-(2-hydroxypropan-2-yl)-phenyl)-5,7-diazaspiro[3.4]octan-6-one-   cis-2-(dimethylamino)-5-((3-fluorooxetan-3-yl)methyl)-2-phenyl-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one-   cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-((6-(rifluoromethyl)pyridin-3-yl)methyl)-5,7-diazaspiro[3.4]octan-6-one-   cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(2-(methylsulfonyl)ethyl)-5,7-diazaspiro[3.4]octan-6-one-   cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one-   cis-5-(cyclopropylmethyl)-2-(dimethylamino)-7-((3-fluorooxetan-3-yl)methyl)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one-   cis-5-(cyclopropylmethyl)-7-(6-cyclopropylpyridin-3-yl)-2-(dimethylamino)-2-phenyl-5,7-diaza-spiro[3.4]octan-6-one-   cis-7-(6-cyclopropyl-4-methylpyridin-3-yl)-5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one-   cis-7-(6-cyclopropyl-4-methylpyridin-3-yl)-2-(dimethylamino)-5-((3-fluorooxetan-3-yl)methyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one-   cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(2-methoxy-2-methylpropyl)-5,7-diazaspiro[3.4]octan-6-one-   cis-2-(dimethylamino)-2-phenyl-7-(2-pyridin-4-ylpyrimidin-5-yl)-5,7-diazaspiro[3.4]octan-6-one-   cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-7-[5-(trifluoromethyl)pyridin-3-yl]-5,7-diazaspiro[3.4]octan-6-one-   cis-5-[5-(cyclopropylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile-   cis-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-morpholinobenzyl)-5,7-diazaspiro[3.4]octan-6-one-   cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-[(1-hydroxycyclobutyl)methyl]-5,7-diazaspiro[3.4]octan-6-one-   cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-7-(2-pyridin-4-ylpyrimidin-5-yl)-5,7-diazaspiro[3.4]octan-6-one-   cis-3-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)propanenitrile-   cis-3-[5-(cyclopropylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl]-propanenitrile-   cis-5-(cyclopropylmethyl)-2-(dimethylamino)-7-[(1-hydroxycyclobutyl)methyl]-2-phenyl-5,7-diaza-spiro[3.4]octan-6-one-   cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-[2-(oxetan-3-yl)ethyl]-5,7-diaza-spiro[3.4]octan-6-one    and the physiologically acceptable salts thereof.

In a preferred embodiment, the compounds according to the invention arein the form of the free bases.

In another preferred embodiment, the compounds according to theinvention are in the form of the physiologically acceptable salts.

For the purposes of the description, a “salt” is to be understood asbeing any form of the compound in which it assumes an ionic form or ischarged and is coupled with a counter-ion (a cation or anion) or is insolution. The term is also to be understood as meaning complexes of thecompound with other molecules and ions, in particular complexes whichare associated via ionic interactions. Preferred salts arephysiologically acceptable, in particular physiologically acceptablesalts with anions or acids or also a salt formed with a physiologicallyacceptable acid.

Physiologically acceptable salts with anions or acids are salts of theparticular compound in question with inorganic or organic acids whichare physiologically acceptable, in particular when used in humans and/ormammals. Examples of physiologically acceptable salts of particularacids include but are not limited to salts of hydrochloric acid,sulfuric acid, and acetic acid.

The invention also includes isotopic isomers of a compound according tothe invention, wherein at least one atom of the compound is replaced byan isotope of the respective atom which is different from the naturallypredominantly occurring isotope, as well as any mixtures of isotopicisomers of such a compound. Preferred isotopes are ²H (deuterium), ³H(tritium), ¹³C and ¹⁴C.

Certain compounds according to the invention are useful for modulating apharmacodynamic response from one or more opioid receptors (mu, delta,kappa, NOP/ORL-1) either centrally or peripherally, or both. Thepharmacodynamic response may be attributed to the compound eitherstimulating (agonizing) or inhibiting (antagonizing) the one or morereceptors. Certain compounds according to the invention may antagonizeone opioid receptor, while also agonizing one or more other receptors.Compounds according to the invention having agonist activity may beeither full agonists or partial agonists.

As used herein, compounds that bind to receptors and mimic theregulatory effects of endogenous ligands are defined as “agonists”.Compounds that bind to a receptor but produce no regulatory effect, butrather block the binding of ligands to the receptor, are defined as“antagonists”.

In certain embodiments, the compounds according to the invention areagonists at the mu opioid (MOP) and/or kappa opioid (KOP) and/or deltaopioid (DOP) and/or nociceptin opioid (NOP/ORL-1) receptors.

The compounds according to the invention potently bind to the MOP and/orKOP and/or DOP and/or NOP receptors.

The compounds according to the invention can be modulators at the MOPand/or KOP and/or DOP and/or NOP receptors, and therefore the compoundsaccording to the invention can be used/administered to treat,ameliorate, or prevent pain.

In some embodiments, the compounds according to the invention areagonists of one or more opioid receptors. In some embodiments, thecompounds according to the invention are agonists of the MOP and/or KOPand/or DOP and/or NOP receptors.

In some embodiments, the compounds according to the invention areantagonists of one or more opioid receptors. In some embodiments, thecompounds according to the invention are antagonists of the MOP and/orKOP and/or DOP and/or NOP receptors.

In some embodiments, the compounds according to the invention have both,(i) agonist activity at the NOP receptor; and (ii) agonist activity atone or more of the MOP, KOP, and DOP receptors.

In some embodiments, the compounds according to the invention have both,(i) agonist activity at the NOP receptor; and (ii) antagonist activityat one or more of the MOP, KOP, and DOP receptors.

In some embodiments, the compounds according to the invention have both,(i) antagonist activity at the NOP receptor; and (ii) agonist activityat one or more of the MOP, KOP, and DOP receptors.

In some embodiments, the compounds according to the invention have both,(i) antagonist activity at the NOP receptor; and (ii) antagonistactivity at one or more of the MOP, KOP, and DOP receptors.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention haveselective agonist activity at the NOP receptor. In some embodiments,preferably with respect to receptors of the peripheral nervous system,the compounds according to the invention

-   -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the KOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the DOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the DOP receptor; or    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor as well as no significant activity at the        DOP receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention havebalanced agonist activity at the NOP receptor as well as at the MOPreceptor. In some embodiments, preferably with respect to receptors ofthe peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor as well as agonist activity at the        KOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor as well as agonist activity at the        DOP receptor;    -   can be regarded as opioid pan agonists, i.e. have agonist        activity at the NOP receptor as well as agonist activity at the        MOP receptor as well as agonist activity at the KOP receptor as        well as agonist activity at the DOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor, but no significant activity at the        KOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor, but no significant activity at the        DOP receptor; or    -   have agonist activity at the NOP receptor as well as agonist        activity at the MOP receptor, but no significant activity at the        KOP receptor as well as no significant activity at the DOP        receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention havebalanced agonist activity at the NOP receptor as well as at the KOPreceptor. In some embodiments, preferably with respect to receptors ofthe peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor as well as agonist activity at the        MOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor as well as agonist activity at the        DOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor, but no significant activity at the        MOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor, but no significant activity at the        DOP receptor; or    -   have agonist activity at the NOP receptor as well as agonist        activity at the KOP receptor, but no significant activity at the        MOP receptor as well as no significant activity at the DOP        receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention havebalanced agonist activity at the NOP receptor as well as at the DOPreceptor. In some embodiments, preferably with respect to receptors ofthe peripheral nervous system, the compounds according to the invention

-   -   have agonist activity at the NOP receptor as well as agonist        activity at the DOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        MOP receptor;    -   have agonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        KOP receptor; or    -   have agonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        MOP receptor as well as no significant activity at the KOP        receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention haveselective agonist activity at the KOP receptor. In some embodiments,preferably with respect to receptors of the peripheral nervous system,the compounds according to the invention

-   -   have agonist activity at the KOP receptor, but no significant        activity at the MOP receptor;    -   have agonist activity at the KOP receptor, but no significant        activity at the NOP receptor;    -   have agonist activity at the KOP receptor, but no significant        activity at the DOP receptor;    -   have agonist activity at the KOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the NOP receptor;    -   have agonist activity at the KOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the DOP receptor; or    -   have agonist activity at the KOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the NOP receptor as well as no significant activity at the        DOP receptor.

In some embodiments, preferably with respect to receptors of theperipheral nervous system, the compounds according to the invention haveagonist activity at the MOP receptor, agonist activity at the KOPreceptor, and antagonist activity at the DOP receptor. In someembodiments, preferably with respect to receptors of the peripheralnervous system, the compounds according to the invention

-   -   have agonist activity at the MOP receptor as well as agonist        activity at the KOP receptor as well as antagonist activity at        the DOP receptor;    -   have agonist activity at the MOP receptor as well as agonist        activity at the KOP receptor as well as antagonist activity at        the DOP receptor as well as agonist activity at the NOP        receptor;    -   have agonist activity at the MOP receptor as well as agonist        activity at the KOP receptor as well as antagonist activity at        the DOP receptor as well as antagonist activity at the NOP        receptor; or    -   have agonist activity at the MOP receptor as well as agonist        activity at the KOP receptor as well as antagonist activity at        the DOP receptor, no significant activity at the NOP receptor.

In some embodiments, preferably with respect to receptors of the centralnervous system, the compounds according to the invention have selectiveagonist activity at the NOP receptor. In some embodiments, preferablywith respect to receptors of the central nervous system, the compoundsaccording to the invention

-   -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the KOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the DOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor;    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the DOP receptor; or    -   have agonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor as well as no significant activity at the        DOP receptor.

In some embodiments, preferably with respect to receptors of the centralnervous system, the compounds according to the invention have selectiveantagonist activity at the NOP receptor. In some embodiments, preferablywith respect to receptors of the central nervous system, the compoundsaccording to the invention

-   -   have antagonist activity at the NOP receptor, but no significant        activity at the MOP receptor;    -   have antagonist activity at the NOP receptor, but no significant        activity at the KOP receptor;    -   have antagonist activity at the NOP receptor, but no significant        activity at the DOP receptor;    -   have antagonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor;    -   have antagonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the DOP receptor; or    -   have antagonist activity at the NOP receptor, but no significant        activity at the MOP receptor as well as no significant activity        at the KOP receptor as well as no significant activity at the        DOP receptor.

In some embodiments, preferably with respect to receptors of the centralnervous system, the compounds according to the invention have antagonistactivity at the NOP receptor as well as agonist activity at the DOPreceptor. In some embodiments, preferably with respect to receptors ofthe central nervous system, the compounds according to the invention

-   -   have antagonist activity at the NOP receptor as well as agonist        activity at the DOP receptor;    -   have antagonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        MOP receptor;    -   have antagonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        KOP receptor; or    -   have antagonist activity at the NOP receptor as well as agonist        activity at the DOP receptor, but no significant activity at the        MOP receptor as well as no significant activity at the KOP        receptor.

For the purpose of the specification, “no significant activity” meansthat the activity (agonist/antagonist) of the given compound at thisreceptor is lower by a factor of 1000 or more compared to its activity(agonist/antagonist) at one or more of the other opioid receptors.

A further aspect of the invention relates to the compounds according tothe invention as medicaments.

A further aspect of the invention relates to the compounds according tothe invention for use in the treatment of pain. A further aspect of theinvention relates to a method of treating pain comprising theadministration of a pain alleviating amount of a compound according tothe invention to a subject in need thereof, preferably to a human. Thepain is preferably acute or chronic. The pain is preferably nociceptiveor neuropathic.

A further aspect of the invention relates to the compounds according tothe invention for use in the treatment of neurodegenerative disorders,neuroinflammatory disorders, neuropsychiatric disorders, and substanceabuse/dependence. A further aspect of the invention relates to a methodof treating any one of the aforementioned disorders, diseases orconditions comprising the administration of a therapeutically effectiveamount of a compound according to the invention to a subject in needthereof, preferably to a human.

Another aspect of the invention relates to a pharmaceutical compositionwhich contains a physiologically acceptable carrier and at least onecompound according to the invention.

Preferably, the composition according to the invention is solid, liquidor pasty; and/or contains the compound according to the invention in anamount of from 0.001 to 99 wt. %, preferably from 1.0 to 70 wt. %, basedon the total weight of the composition.

The pharmaceutical composition according to the invention can optionallycontain suitable additives and/or auxiliary substances and/or optionallyfurther active ingredients.

Examples of suitable physiologically acceptable carriers, additivesand/or auxiliary substances are fillers, solvents, diluents, coloringsand/or binders. These substances are known to the person skilled in theart (see H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetikand angrenzende Gebiete, Editio Cantor Aulendoff).

The pharmaceutical composition according to the invention contains thecompound according to the invention in an amount of preferably from0.001 to 99 wt. %, more preferably from 0.1 to 90 wt. %, yet morepreferably from 0.5 to 80 wt. %, most preferably from 1.0 to 70 wt. %and in particular from 2.5 to 60 wt. %, based on the total weight of thepharmaceutical composition.

The pharmaceutical composition according to the invention is preferablyfor systemic, topical or local administration, preferably for oraladministration.

Another aspect of the invention relates to a pharmaceutical dosage formwhich contains the pharmaceutical composition according to theinvention.

In one preferred embodiment, the pharmaceutical dosage form according tothe invention is produced for administration twice daily, foradministration once daily or for administration less frequently thanonce daily. Administration is preferably systemic, in particular oral.

The pharmaceutical dosage form according to the invention can beadministered, for example, as a liquid dosage form in the form ofinjection solutions, drops or juices, or as a semi-solid dosage form inthe form of granules, tablets, pellets, patches, capsules,plasters/spray-on plasters or aerosols. The choice of auxiliarysubstances etc. and the amounts thereof to be used depend on whether theform of administration is to be administered orally, perorally,parenterally, intravenously, intraperitoneally, intradermally,intramuscularly, intranasally, buccally, rectally or locally, forexample to the skin, the mucosa or into the eyes.

Pharmaceutical dosage forms in the form of tablets, dragees, capsules,granules, drops, juices and syrups are suitable for oral administration,and solutions, suspensions, readily reconstitutable dry preparations andalso sprays are suitable for parenteral, topical and inhalatoryadministration. Compounds according to the invention in a depot, indissolved form or in a plaster, optionally with the addition of agentspromoting penetration through the skin, are suitable percutaneousadministration preparations.

The amount of the compounds according to the invention to beadministered to the patient varies in dependence on the weight of thepatient, on the type of administration, on the indication and on theseverity of the disease. Usually, from 0.00005 mg/kg to 50 mg/kg,preferably from 0.001 mg/kg to 10 mg/kg, of at least one compoundaccording to the invention is administered.

Another aspect of the invention relates to a process for the preparationof the compounds according to the invention. Suitable processes for thesynthesis of the compounds according to the invention are known inprinciple to the person skilled in the art.

EXAMPLES

The following examples further illustrate the invention but are not tobe construed as limiting its scope.

“RT” means room temperature (23±7° C.), “M” are indications ofconcentration in mol/l, “aq.” means aqueous, “sat.” means saturated,“sol.” means solution, “conc.” means concentrated.

Further abbreviations:

-   brine saturated aqueous sodium chloride solution-   Boc₂O di-tert-butyl dicarbonate-   Bu butyl-   DCM dichloromethane-   DIPEA N,N-diisopropylethylamine-   DMSO dimethylsulfoxide-   DMF N,N-dimethylformamide-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)-   Et ethyl-   ether diethyl ether-   EtOAc ethyl acetate-   EtOH ethanol-   h hour(s)-   HATU    O-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate-   LDA lithium diisoproylamide-   Me methyl-   m/z mass-to-charge ratio-   MeOH methanol-   MeCN acetonitrile-   min minutes-   MS mass spectrometry-   NBS N-bromosuccinimide-   NIS N-iodosuccinimide-   NEt₃ triethylamine-   TFA trifluoroacetic acid-   T3P    2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide-   THF tetrahydrofurane-   v/v volume to volume-   w/w weight to weight-   Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

The yields of the compounds prepared were not optimised. Alltemperatures are uncorrected.

All starting materials, which are not explicitly described, were eithercommercially available (the details of suppliers such as for exampleAcros, Aldrich, Bachem, Butt park, Enamine, Fluka, Lancaster, Maybridge,Merck, Sigma, TCI, Oakwood, etc. can be found in the Symyx® AvailableChemicals Database of MDL, San Ramon, US or the SciFinder® Database ofthe ACS, Washington D.C., US, respectively, for example) or thesynthesis thereof has already been described precisely in the specialistliterature (experimental guidelines can be found in the Reaxys® Databaseof Elsevier, Amsterdam, NL or the SciFinder® Database of the ACS,Washington D.C., US, respectively, for example) or can be prepared usingthe conventional methods known to the person skilled in the art.

The mixing ratios of solvents or eluents for chromatography arespecified in v/v.

All the intermediate products and exemplary compounds were analyticallycharacterised by mass spectrometry (MS, m/z for [M+H]⁺). In addition¹H-NMR and ¹³C spectroscopy was carried out for all the exemplarycompounds and selected intermediate products.

Synthetic Procedures for the Preparation of Intermediates General Schemefor the Synthesis of INT-7 and INT-8

3-(Benzyloxy)-1-(dimethylamino)cyclobutanecarbonitrile (INT-1)

This reaction was carried out under N₂ in a 5 L 3-neck round bottomflask. To 3-(benzyloxy)cyclobutan-1-one (88 g, 499 mmol) was added MeOH(88 mL), followed by Me₂NH.HCl (116 g, 1423 mmol). After stirring at RTfor 10 min, 40% aqueous Me₂NH (626 mL, 4939 mmol) was added followed byNaCN (26.9 g, 549 mmol). The reaction mixture was stirred at RTovernight. The reaction mixture was diluted with sat aq NaHCO₃ (400 mL)and water (400 mL) and extracted with EtOAc (4×800 mL). The combinedorganic extracts were dried over Na₂SO₄, filtered, and the filtrate wasconcentrated under reduced pressure. The residue was co-evaporated twicewith THF affording3-(benzyloxy)-1-(dimethylamino)cyclobutanecarbonitrile (INT-1) (122.9 g(80% pure), 427 mmol, 85%) as a brown oil which was used in the nextstep without further purification. LCMS: calculated for [M+H]⁺=231.2,found 231.1.

3-(Benzyloxy)-N,N-dimethyl-1-phenylcyclobutanamine (INT-2)

This reaction was carried out under N₂. The reaction flask was dried(heat-gun) before use. 3 M PhMgBr in Et₂O (1.423 L, 4269 mmol) wascooled to −10° C. A solution of3-(benzyloxy)-1-(dimethylamino)cyclobutanecarbonitrile (INT-1) (122.9 g(80% pure), 427 mmol) in dry THF (1.0 L) was added dropwise over ca. 70min at −10° C. and stirring at −10° C. to 0° C. was continued for 3 hafter complete addition of the starting material. Upon cooling on icebath, the reaction mixture was carefully quenched by the dropwiseaddition of a solution of 660 g of NH₄Cl (12.3 mol) in H₂O (2.6 L).After complete addition, EtOAc (1.7 L) was added, the mixture wasstirred for 30 min and the layers were separated. EtOAc (1.7 L) wasadded to the aqueous phase and the mixture was stirred for 30 min andleft standing overnight. Layers were separated. EtOAc (1.7 L) was addedto the aqueous phase, the mixture was stirred for 30 min and the layerswere separated. EtOAc (1.7 L) was added to the aqueous phase and themixture was stirred for 30 min and the layers were separated. Allorganic layers were combined and evaporated under reduced pressure. Theproduct was purified by column chromatography (1.2 kg silica,heptane/EtOAc, 9:1→1:1→1:2→0:1), to give 58.15 g (207 mmol, 48.4%) of3-(benzyloxy)-N,N-dimethyl-1-phenylcyclobutanamine (INT-2). LCMS:calculated for [M+H]⁺=282.2, found 282.2.

3-(Dimethylamino)-3-phenylcyclobutanol (INT-3)

This reaction was carried out under N₂. At 0° C., 1 M BCl₃ in DCM (349mL, 349 mmol) was added dropwise over ca. 45 min to a solution of3-(benzyloxy)-N,N-dimethyl-1-phenylcyclobutanamine (INT-2) (65.39 g, 232mmol) in DCM (650 mL). Stirring at 0° C. was continued for 30 min. More1 M BCl₃ in DCM (349 mL, 349 mmol) was added dropwise over 45 min andstirring was continued at 0° C. for 1 h. MeOH (ca. 200 mL) was addeddropwise at 0° C. and the solvent was removed under reduced pressure at30° C. The crude product was concentrated again from MeOH (3×). Thecrude product was dissolved in DCM (200 mL) and MeOH (200 mL). Silica(200 g) was added and the solvent was removed under reduced pressure.The product was purified by column chromatography (silica, DCM/(7M NH₃in MeOH), 1:0→98:2→95:5→93:7→9:1), to obtain3-(dimethylamino)-3-phenylcyclobutanol (INT-3) (37.53 g, 196 mmol, 84%).LCMS: calculated for [M+H]⁺=192.1, found 192.2.

3-(Methylamino)-3-phenylcyclobutanol (INT-4)

To 3-(dimethylamino)-3-phenylcyclobutanol (INT-3) (44.44 g, 232 mmol)was added dry MeCN (2.25 L) and the resulting suspension was stirred atRT overnight to dissolve most of the starting material.N-iodosuccinimide (57.5 g, 256 mmol) was added portionwise over ca. 10min and the reaction mixture was stirred at RT for 2 h. MoreN-iodosuccinimide (15.68 g, 69.7 mmol) was added portionwise over ca. 5min and stirring at RT was continued for 2.5 h. The solvent was removedunder reduced pressure. The crude product was purified by columnchromatography (silica, DCM/(7M NH₃ in MeOH), 1:0→98:2→95:5→9:1) to givea reasonably pure batch of 3-(methylamino)-3-phenylcyclobutanol (INT-4)(8.19 g (73% pure), 33.7 mmol, 14.5%) and a very impure batch of INT-4(78 g (ca. 9% pure)). The very impure batch was purified further bycolumn chromatography (silica, DCM/MeOH/Et₃N, 90:9:1) to give anotherbatch of INT-4 (27.7 g (23% pure), 35.9 mmol, 15.5%). Total yield: 30%.LCMS: calculated for [M+H]⁺=178.1, found 178.2.

Tert-butyl (3-hydroxy-1-phenylcyclobutyl)(methyl)carbamate (INT-5)

To a solution of 3-(methylamino)-3-phenylcyclobutanol (INT-4) (8.15 g(73% pure), 33.6 mmol) and Et₃N (23.39 mL, 168 mmol) in DCM (50 mL) wasadded Boc₂O (8.06 g, 36.9 mmol) and the reaction mixture was stirred atRT overnight. More Boc₂O (8.06 g, 36.9 mmol) was added and stirring atRT was continued for 6 h. The solvent was removed under reducedpressure. The product was purified by column chromatography (1 kgsilica, DCM/MeOH, 1:0→98:2), to afford a pure batch of tert-butyl(3-hydroxy-1-phenylcyclobutyl)(methyl)carbamate (INT-5) (5.89 g, 21.2mmol, 63.3%) and an impure batch of INT-5 (2.36 g (71% pure), 6.04 mmol,18.0%). Total yield: 81%. LCMS: calculated for [M+H-^(t)Bu]⁺=222.1,found 222.1.

Tert-butyl methyl(3-oxo-1-phenylcyclobutyl)carbamate (INT-6)

To a solution of tert-butyl(3-hydroxy-1-phenylcyclobutyl)(methyl)carbamate (INT-5) (5.89 g, 21.24mmol) in DCM (90 mL) was added Et₃N (17.76 mL, 127 mmol) and DMSO (12.06mL, 170 mmol) followed by pyridine SO₃ (10.14 g, 63.7 mmol). Thereaction mixture was stirred at RT overnight. Sat. aq. NH₄Cl (50 mL) andwater (50 mL) was added. Layers were separated and the aqueous layer wasextracted with DCM (60 mL). Organic layers were combined, washed withsat. aq. NaHCO₃ (100 mL), dried over Na₂SO₄ and evaporated under reducedpressure. The crude product was purified by flash chromatography (120 gsilica, gradient heptane/EtOAc, 95:5-3:2). The resulting product wasconcentrated from EtOH to afford tert-butylmethyl(3-oxo-1-phenylcyclobutyl)carbamate (INT-6) (4.50 g, 16.34 mmol,77%). LCMS: calculated for [M+H-^(t)Bu]⁺=220.1, found 220.1.

Tert-butylcis-(6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]octan-2-yl)(methyl)carba-mate(INT-7) and tert-butyltrans-(6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]octan-2-yl)(methyl)carbamate(INT-8)

This reaction was carried out in a closed system (500 mL glass Parrsystem). To a mixture of (NH₄)₂CO₃ (13.09 g, 136 mmol) and KCN (1.774 g,27.2 mmol) was added a solution of tert-butylmethyl(3-oxo-1-phenylcyclobutyl)carbamate (INT-6) (7.5 g, 27.2 mmol) inEtOH (60 mL). H₂O (60 mL) was added and the reaction mixture was stirredat 70° C. overnight. The white suspension was allowed to cool to RT.Crushed ice (˜60 mL) was added and the obtained mixture was filteredover a sintered glass filter (P3). The flask was rinsed with a mixtureof EtOH/H₂O (50 mL, 1/1, v/v), which was also filtered. To the combinedfiltrate was added aq. sat. NaHCO₃ (300 mL) and the mixture wasextracted with DCM (3×300 mL). The combined organic layers were dried(Na₂SO₄) and concentrated. Purification by flash chromatography (220 gsilica, gradient heptane/EtOAc, 3:2→0:1) followed by co-evaporation withEt₂O (2×30 mL) afforded tert-butyltrans-(6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]octan-2-yl)(methyl)carbamate(INT-8) (5.53 g, 16.01 mmol, 59%). LCMS: calculated for [M−H]⁻=344.2,found 344.2. The residue on the glass filter was washed with a mixtureof EtOH/H₂O (120 mL, 1/1, v/v) and was dried on the filter by vacuumunder a N₂ stream to yield tert-butylcis-(6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]octan-2-yl)(methyl)carbamate(INT-7) (3.05 g, 8.83 mmol, 32%). LCMS: calculated for [M−H]⁻=344.2,found 344.2.

General Scheme for the Synthesis of INT-13

Tert-butylcis-(7-(4-methoxybenzyl)-6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]-octan-2-yl)(methyl)-carbamate(INT-9)

Dry glassware and argon atmosphere were used. To a suspension oftert-butylcis-(6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]octan-2-yl)(methyl)carbamate(INT-7) (0.3 g, 0.869 mmol) and 4-methoxybenzyl chloride (0.124 mL,0.912 mmol) in anhydrous DMF (15 mL) was added K₂CO₃ (0.126 g, 0.912mmol) and the mixture was stirred at RT overnight. Additional K₂CO₃(0.012 g, 0.087 mmol) and 4-methoxybenzyl chloride (0.012 mL, 0.087mmol) were added and the mixture was stirred at RT for another 4 h. Thereaction mixture was partitioned between brine (200 mL) and EtOAc (100mL). The water layer was extracted with EtOAc (3×100 mL). Combinedorganic layers were washed with brine (3×100 mL) and dried overNa₂SO₄(s). In vacuo concentration gave a colourless oil as crudeproduct. This experiment was repeated in the same way using 1.62 g (4.68mmol) of tert-butylcis-(6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]octan-2-yl)(methyl)carbamate(INT-7). The obtained crude products were combined for purification byflash chromatography (120 g silica, gradient heptane/EtOAc, 20:1→3:7)and afforded tert-butylcis-(7-(4-methoxybenzyl)-6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]-octan-2-yl)(methyl)carbamate(INT-9) (2.09 g, 4.489 mmol, 81%). LCMS: calculated for [M+H]⁺=466.5,found 466.3.

Tert-butylcis-(5-(cyclobutylmethyl)-7-(4-methoxybenzyl)-6,8-dioxo-2-phenyl-5,7-diaza-spiro[3.4]octan-2-yl)(methyl)carbamate(INT-10)

Dry glassware and argon atmosphere were used. To a solution oftert-butylcis-(7-(4-methoxybenzyl)-6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]-octan-2-yl)(methyl)carbamate(INT-9) (200 mg, 0.430 mmol) in anhydrous DMF (8 mL) was added 60% NaHin mineral oil (34.4 mg, 0.859 mmol) and the mixture was stirred at RTuntil gas evolution ceased. Then, (bromomethyl)cyclobutane (0.191 mL,1.718 mmol) was added and stirring was continued at RT for 4 h. Thereaction mixture was cooled in an ice-bath and carefully quenched withwater (2 mL) and diluted with brine (100 mL) and EtOAc (20 mL). Layerswere partitioned and the water layer was extracted with EtOAc (3×20 mL).Combined organic layers were washed with brine and dried over Na₂SO₄(s).Filtration followed by in vacuo filtrate concentration gave a colorlessoil as crude product. This experiment was repeated in the same way using1.81 g (3.89 mmol) of tert-butylcis-(7-(4-methoxybenzyl)-6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]-octan-2-yl)(methyl)carba-mate(INT-9). However, quenching was performed with MeOH (1 mL) instead ofwater. The obtained crude products were combined for purification byflash chromatography (120 g silica, gradient heptane/EtOAc, 9:1→1:1),which afforded tert-butylcis-(5-(cyclobutylmethyl)-7-(4-methoxybenzyl)-6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]octan-2-yl)(methyl)carbamate(INT-10) (1.92 g, 3.587 mmol, 83%) as a white foamy solid. LCMS:calculated for [M+H]⁺=534.7, found 534.4.

Cis-5-(cyclobutylmethyl)-2-(methylamino)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione(INT-11)

Dry glassware and an inert atmosphere (Ar(g)) were used. To a solutionof tert-butylcis-(5-(cyclobutylmethyl)-7-(4-methoxybenzyl)-6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]octan-2-yl)(methyl)carbamate(INT-10) (2.022 g, 3.79 mmol) in extra dry anisole (60 mL) was addedAlCl₃ (2.53 g, 18.94 mmol) and the resulting colourless solution wasstirred at 75° C. for 1.5 h. Then after cooling down to RT, additionalAlCl₃ (2.53 g, 18.94 mmol) was added and stirring at 75° C. wascontinued overnight. The reaction mixture was cooled down to RT andquenched by adding the reaction mixture to sat. aq. Na₂CO₃ (400 mL).Brine (150 mL) and EtOAc (400 mL) were added and the layers wereseparated. The aqueous phase was extracted with EtOAc (3×100 mL). Thecombined organic layers were washed with brine (200 mL) and dried overNa₂SO₄(s). Filtration followed by in vacuo filtrate concentration gave abrown oil as crude product. The obtained crude product was loaded ontosilica and purified by flash chromatography (120 g silica, gradientheptane/EtOAc, 3:1→3:7) which affordedcis-5-(cyclobutylmethyl)-2-(methylamino)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione(INT-11) (998 mg, 3.185 mmol, 84%) as a yellowish solid. LCMS:calculated for [M+H]⁺=314.4, found 314.2. ¹H-NMR (400 MHz, CDCl₃) δ 7.62(bs, 1H), 7.36 (t, J=7.5 Hz, 2H), 7.30-7.19 (m, 3H), 3.80 (d, J=7.4 Hz,2H), 3.07 (d, J=14.2 Hz, 2H), 2.85 (m, 1H), 2.56 (d, J=14.2 Hz, 2H),2.07 (m, 5H), 1.89 (m, 4H).

Cis-5-(cyclobutylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]-octane-6,8-dione(INT-12)

To a solution ofcis-5-(cyclobutylmethyl)-2-(methylamino)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione(INT-11) (200 mg, 0.638 mmol) in 2-propanol (10 mL) was added slowlyformic acid (0.240 mL, 6.38 mmol) and the mixture was stirred at 65° C.At the same temperature, 37% aqueous formaldehyde (0.480 mL, 6.38 mmol)was added at once and stirring was continued at the same temperatureovernight. The reaction mixture was cooled down to RT and the reactionwas carefully quenched with sat. aq. NaHCO₃. The mixture was thendiluted with brine and DCM. Layers were separated using a phaseseparator and the aqueous phase was extracted with DCM (2×15 mL). Thecombined organic layers were concentrated under reduced pressure toafford the crude product as a brownish sticky oil. The crude product wassubjected to a purification by flash column chromatography (12 g silica,gradient DCM/MeOH, 199:1→97:3) affording a more pure product.Subsequently, this material was subjected to a second purification bypreparative HPLC (HPLC instrument type: Agilent Technologies 1200preparative LC; column: Waters XSelect CSH (C18, 150×25 mm, 10); flow:43 mL/min; column temp: RT; eluent A: 99% acetonitrile+1% 10 mM ammoniumbicarbonate in water pH=9.0, eluent B: 10 mM ammonium bicarbonate inwater pH=9.0; lin. gradient: t=0 min 20% A, t=2.5 min 20% A, t=11 min60% A, t=13 min 100% A, t=17 min 100% A; detection: DAD (210 nm)) toobtaincis-5-(cyclobutylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]-octane-6,8-dione(INT-12) as a white solid (98 mg, 0.30 mmol, 47%). LCMS: calculated for[M+H]⁺=328.4, found 328.2. ¹H-NMR (400 MHz, CDCl₃) 7.35 (m, 3H), 7.28(m, 1H), 7.05-7.03 (m, 2H), 3.71 (d, J=7.4 Hz, 2H), 3.02 (d, J=14.0 Hz,2H), 2.86-2.78 (m, 1H), 2.71 (d, J=14.0 Hz, 2H), 2.12-2.06 (m, 2H), 1.94(s, 6H), 1.94-1.77 (m, 4H).

Cis-5-(cyclobutylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]-octan-6-one(INT-13)

Oven dried glassware and an inert atmosphere were used. To an ice-bathcooled solution of AlCl₃ (586 mg, 4.40 mmol) in dry THF (8 mL) wascarefully and dropwise added 2.4 M LiAlH₄ in THF (1.374 mL, 3.30 mmol)and the reaction mixture was stirred at RT for 30 min. Then, the mixturewas re-cooled in an ice-bath and a solution ofcis-5-(cyclobutylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]-octane-6,8-dione(INT-12) (360 mg, 1.099 mmol) in dry THF (14 mL) was added dropwise. Themixture was stirred at the same temperature for 1 h and at RT for 3 h.The reaction mixture was cooled in an ice bath and the reaction wascarefully quenched by the dropwise addition of water (20 mL). Aqueous 1M NaOH (30 mL) and DCM (25 mL) were added and the layers were separatedusing a phase separator. The water layer was extracted with DCM (4×10mL). In vacuo concentration of the combined organic layers gave thecrude product as a white solid. The obtained crude product was purifiedby flash chromatography (40 g silica, gradient DCM/MeOH, 199:1→93:7) andaffordedcis-5-(cyclobutylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]-octan-6-one(INT-13) (311 mg, 0.992 mmol, 90%). LCMS: calculated for [M+H]⁺=314.4,found 314.3. ¹H NMR (400 MHz, CDCl₃) δ: 7.37 (m, 2H), 7.33-7.27 (m, 1H),7.25-7.18 (m, 2H), 4.12 (s, 1H), 3.29 (d, J=7.3 Hz, 2H), 2.85 (d, J=1.2Hz, 2H), 2.72-2.59 (m, 3H), 2.58-2.49 (m, 2H), 2.03 (m, 2H), 1.94 (s,6H), 1.90-1.76 (m, 4H).

Cis-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (INT-14)

To a cooled (0° C.) suspension of tert-butylcis-(6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]octan-2-yl)(methyl)carbamate(INT-7) (250 mg, 0.724 mmol) in dry THF (2.5 mL) was dropwise added 2.4M LiAlH₄ in THF (1.206 mL, 2.90 mmol). The mixture was stirred underreflux for 2 d. After cooling to RT, the mixture was diluted with THF (5mL) and carefully quenched with Na₂SO₄.10H₂O. The mixture was dilutedfurther with THF (15 mL) and stirred at RT for ca. 1 h. The mixture wasfiltered over a layer of Na₂SO₄ and rinsed with THF (10 mL) and DCM (25mL). The combined filtrate was concentrated to dryness. The residue ofthe filtration was then stirred in MeOH/THF (1:1, v/v, 40 mL), filteredand the filtrate was combined with the first batch of crude product andconcentrated to dryness. The product was triturated with hot DMSO. Afterfiltration, the residue was washed with a small amount of Et₂O and driedunder reduced pressure with a flow of N₂ to givecis-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (INT-14)(94.2 mg, 0.384 mmol, 53%). LCMS: calculated for [2M+Na]⁺=513, found513.3. ¹H NMR (400 MHz, DMSO-d₆) δ 7.38 (m, 2H), 7.28 (m, 3H), 6.70 (s,1H), 5.98 (s, 1H), 2.77-2.65 (m, 4H), 2.33 (d, J=11.4 Hz, 2H), 1.81 (s,6H).

Tert-butylcis-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetate(INT-15)

To a suspension ofcis-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (INT-14)(260 mg, 1.06 mmol) in dry DMF (26 mL), a solution of 1.65 M solution ofKOtBu in THF (0.642 mL, 1.06 mmol) was added dropwise under a N₂atmosphere. After ˜10 min a solution of tert-butyl bromoacetate (0.188mL, 1.27 mmol) in DMF (5 mL) was added dropwise and the solution wasstirred at RT for 30 min. Solid NH₄Cl (193 mg, 3.60 mmol) was added andafter ˜20 min the suspension was filtered. The residue was rinsed withMeCN (30 mL) and the combined filtrates were concentrated. The residuewas loaded on silica using MeOH/DCM. Purification by flashchromatography (40 g silica, gradient DCM/(7 M NH₃ in MeOH), 99:1 to9:1) afforded tert-butylcis-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetate(INT-15) (142 mg, 0.40 mmol, 37%). LCMS: calculated for [M+H]⁺=360.5,found 360.3.

Cis-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)aceticacid (INT-16)

To a solution of tert-butylcis-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetate(INT-15) (141 mg, 0.392 mmol) in DCM (3 mL) was added TFA (3.02 mL, 39.2mmol) and the mixture was stirred at RT. After 2 h the mixture wasconcentrated and the crude product was concentrated again from DCMsolution (2×, 10 mL each) to yield crudecis-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)aceticacid (INT-16) (240 mg) which was used in the next step without furtherpurification. LCMS: calculated for [M+H]⁺=304.2, found 304.2.

Tert-butylcis-2-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro-[3.4]octan-7-yl)acetate(INT-25)

Oven dried glassware and an inert atmosphere Ar(g) were used. To asolution ofcis-5-(cyclobutylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]-octan-6-one(INT-13) (20 mg, 0.064 mmol) in a mixture of dry DMF (1 mL)/dry THF (1mL) at RT was added 60% NaH in mineral oil (3.32 mg, 0.083 mmol). After15 min gas evolution had ceased and a solution of tert-butylbromoacetate (0.014 mL, 0.096 mmol) in dry DMF (1 mL) was added dropwiseand the mixture was stirred at RT for 4 h. The reaction was quenchedcarefully by adding a mixture of brine/water (10 mL, 1/1, v/v). Then,the mixture was diluted with EtOAc (4 mL). The layers were separated andthe water layer was extracted with EtOAc (3×4 mL). Combined organiclayers were concentrated in vacuo (bath temperature 40° C.) to affordthe crude product as a colorless sticky oil. This experiment wasrepeated in the same way on larger scale:cis-5-(cyclobutylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]-octan-6-one(INT-13) (100 mg, 0.319 mmol). The crude products were combined andsubjected to flash chromatography (12 g silica, gradient DCM/MeOH,199:1→193:7) to afford tert-butylcis-2-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro-[3.4]octan-7-yl)acetate(INT-25) as a white solid (135 mg (94% pure), 0.297 mmol, 78/o). LCMS:calculated for [M+H]=428.6, found 428.3.

General Scheme for the Synthesis of INT-34

1-(3-fluorophenyl)-3,3-dimethoxycyclobutanecarbonitrile (INT-27)

A suspension of NaH (110 g, 4580.1 mmol) in DMF (1.6 Lit) was cooled to0° C., prior to the dropwise addition of 2-(3-fluorophenyl)acetonitrile(206 g, 1526.7 mmol) over 2 h. Reaction mixture was brought to rt andstirred for 45 min. To this mixture was added1,3-dibromo-2,2-dimethoxypropane (200 g, 763.3 mmol) in one portion atRT and stirring was continued at RT for 16 h, before heating at 80° C.for 3 h. The reaction mixture was cooled to 0° C. and quenched withcrushed ice water (500 mL) and diluted with water (2.5 L), extractedwith ethyl acetate (2×2 L). The combined organic layer was washed withbrine solution (3×3 L), dried over Na₂SO₄, filtered and the filtrate wasconcentrated. The crude compound was purified by silica gel columnchromatography (100-200 mesh), eluting with 2-3% ethyl acetate inpet-ether to afford 114 g (63%) of1-(3-fluorophenyl)-3,3-dimethoxycyclobutanecarbonitrile (INT-27) as acolorless liquid (TLC system: 15% ethyl acetate in pet ether; Rf: 0.4).

1-(3-fluorophenyl)-3,3-dimethoxycyclobutanecarboxamide (INT-28)

30% H₂O₂ solution (109.9 mL, 970.2 mmol) was added drop wise to amixture of K₂CO₃ (20 g, 145.5 mmol) and1-(3-fluorophenyl)-3,3-dimethoxycyclobutanecarbonitrile (INT-27) (114 g,485.1 mmol) in DMSO (1.14 L) at 40° C. and the reaction mixture washeated at 80° C. for 3 h. The reaction completion was monitored by TLC.The reaction mass was quenched with ice cold water (1 L) and), extractedwith ethyl acetate (3×2 L), washed with brine solution (3×3 L), driedover Na₂SO₄, filtered and the filtrate was concentrated to afford 117 gof 1-(3-fluorophenyl)-3,3-dimethoxycyclobutanecarboxamide (INT-28) (95%)as an off white solid. (TLC system: 70% ethyl acetate in pet ether; Rf:0.6). LCMS: calculated for [M+H]⁺=254.12, found 254.1.

1-(3-fluorophenyl)-3-oxocyclobutanecarboxamide (INT-29)

To a solution of 1-(3-fluorophenyl)-3,3-dimethoxycyclobutanecarboxamide(INT-28) (1.8 g, 7.11 mmol) in acetone (18 mL) was added 6 N HCl (14 mL)at 0° C. and the resulting mixture was stirred at RT for 2 h. Thereaction completion was monitored by TLC. The reaction mixture wasneutralized with 20% NaOH solution up to pH 6 at 0-10° C., and extractedwith ethyl acetate, dried over Na₂SO₄, filtered and the filtrate wasconcentrated to afford 1.4 g of1-(3-fluorophenyl)-3-oxocyclobutanecarboxamide (INT-29) (95%) as a pinksolid. (TLC system: 70% ethyl acetate in pet ether; Rf: 0.7). LCMS:calculated for [M+H]⁺=208.08, found 207.9.

2-(3-fluorophenyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide(INT-30)

To a suspension of 1-(3-fluorophenyl)-3-oxocyclobutanecarboxamide(INT-29) (81 g, 391.30 mmol) in 1620 mL of EtOH:H₂O (1:1 v/v) were addedKCN (35.6 g, 1533.9 mmol) and (NH₄)₂CO₃ (172 g, 1095.6 mmol) at roomtemperature. The reaction mixture was heated at 70° C. for 16 h. Thereaction mixture was cooled to RT, diluted with water (810 mL),neutralized with 6 N HCl up to pH 6 and solid thus precipitated wasfiltered and dried to afford 52 g (47.9%) of2-(3-fluorophenyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide(INT-30) as an off-white solid (3:1 mixture of stereoisomers) (TLC: 10%methanol in dichloromethane; Rf: 0.25-0.40). LCMS: calculated for[M+H]+=278.1, found 277.9.

2-amino-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione (INT-31)

Bis(trifluoroacetoxy)iodo]benzene (93 g, 217.39 mmol) was added to asolution of2-(3-fluorophenyl)-6,8-dioxo-5,7-diazaspiro[3.4]octane-2-carboxamide(INT-30) (50 g, 181.15 mmol) in a mixture of acetonitrile and water(3:1, 2.0 L) at RT. The reaction mixture was stirred at RT for 16 h. Thereaction completion was monitored by TLC. Reaction mixture wasneutralized with aq NaHCO₃ solution till pH 6, extracted with ethylacetate, dried over Na₂SO₄, filtered and the filtrate was concentratedto afford 40 g of2-amino-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione (INT-31)(88%) as an off-white solid (˜1:1 mixture of stereoisomers). (TLC: 10%methanol in dichloromethane; Rf: 0.30-035). LCMS: calculated for[M+H]+=250.1, found 250.0.

2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione(INT-32)

To a solution of2-amino-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione(INT-31)(18 g, 72.28 mmol) in THF (540 L) under argon were added DIPEA(25 mL, 144.57 mmol), MeI (18 mL, 289.15 mmol) and the reaction mixturewas stirred at RT for 16 h. The reaction completion was monitored byLC-MS. The reaction mixture was concentrated under vacuum and trituratedwith water (200 mL) and the resulting solid was filtered to afford 12 g(59%) of2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione(INT-32) as an off-white solid (˜3:5 mixture of stereoisomers). LCMS:calculated for [M+H]+=278.13, found 278.0.

Cis-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione(INT-33)

2-(Dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione(INT-32) (12 g) was purified by chiral SFC to get 6.2 g ofcis-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione(INT-33) as an off-white solid (LC-MS peak-2). Preparative SFCConditions: column: Chiralpak IG (30×250 mm), 5μ; % co-solvent: 30.0%(100% Methanol); % CO₂: 70.0%; total flow: 90.0 g/min; back pressure:90.0 bar; UV: 214 nm; stack time: 10.3 min; load/inj: 103.0 mg;injection solvent: methanol+acetonitrile+THF (2:2:1); No. of injections:140; instrument details:Make/Model: SFC-200-002. ¹H NMR (400 MHz,DMSO-d₆) δ 10.50 (s, 1H), 8.32 (s, 1H), 7.42-7.33 (m, 1H), 7.12-7.08 (m,1H), 6.97-6.89 (m, 2H), 2.86 (d, 2H), 2.51 (d, 2H), 1.88 (s, 6H).

Cis-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one(INT-34)

LiAlH₄ (1 M in THF) (82 mL, 82.31 mmol) was added to a solution ofcis-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione(INT-33) (5.7 g, 20.57 mmol) in THF (228 mL) at 0° C. under argon. Thereaction mixture was stirred at 80° C. for 16 h. The reaction completionwas monitored by TLC. The reaction mixture was cooled to 0° C., quenchedwith saturated Na₂SO₄ solution and diluted with 10% methanol in DCM andfiltered through celite bed. The filtrate was washed with 10% methanolin DCM and the filtrate was concentrated under reduced pressure toafford crude compound. The crude compound was triturated with methanoland diethyl ether successively to get 6 g (LC-MS 82%) of desiredcompound, which was in turn triturated with ethyl acetate to furnish 5.7g (LC-MS 94%) of compound. Another trituration with methanol gave 5.4 g(98%, LC-MS 97%) ofcis-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro [3.4]octan-6-one (INT-34) as an off-white solid. (TLC system: 10% MeOH inDCM, Rf: 0.28). ¹H NMR (DMSO-d₆): δ 7.44-7.38 (m, 1H), 7.13-7.09 (m,3H), 6.69 (s, 1H), 5.99 (s, 1H), 2.72-2.69 (m, 4H), 2.32 (dd, J=2.4 Hz,9.6 Hz, 2H), 1.82 (s, 6H). LCMS: calculated for [M+H]+=264.15, found264.15.

General Scheme for the Synthesis of INT-38 and INT-39

2-(Dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octane-6,8-dione(INT-36)

Cs₂CO₃ (3.3 g, 10.37 mmol) was added to a solution of2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octane-6,8-dione(INT-36) (2.5 g, 9.02 mmol) in acetonitrile (300 mL) under argon andstirred for 15 min at RT, prior to the addition of 4-methoxybenzylbromide (1.42 mL, 9.92 mmol). The reaction mixture was stirred for 16 hat RT. The reaction completion was monitored by TLC. The reaction wasrepeated on the same scale and the reaction mixtures from both batcheswere combined and quenched with saturated NH₄Cl solution (100 mL) andextracted with ethyl acetate (2×100 mL). The organic layer was washedwith brine solution, dried over Na₂SO₄, filtered and the filtrate wasconcentrated to give crude compound. The crude product was purified byneutral alumina column chromatography, eluting with 0.5-1.0% methanol inDCM to afford 4.3 g (60%) of2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octane-6,8-dione(INT-36) as an off-white solid (˜1:1 mixture of stereoisomers) (TLCsystem: 10% MeOH in dichloromethane, Rf: 0.5 and 0.6). LCMS: calculatedfor [M+H]+=398.19, found 397.9

2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octan-6-one(INT-37)

AlCl₃ (5.6 g, 42.11 mmol) was dissolved in THF (300 mL) at 0° C. underargon, prior to the addition of LiAlH₄ (1 M in THF) (44 mL, 44.33 mmol)and the solution was stirred at RT for 1 h. To this mixture was dropwiseadded a solution2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octane-6,8-dione(INT-36) (4.4 g, 11.08 mmol) in THF (100 mL) at 0° C. under argon over 1h. After addition, the reaction mixture was stirred at 80° C. for 16 h.The reaction completion was monitored by LC-MS. The reaction mixture wascooled to 0° C., quenched with sat. aq. NaHCO₃ and diluted with 10%methanol in DCM and filtered through celite bed. The filtrate was washedwith 10% methanol in dichloromethane and the filtrate was concentratedunder reduced pressure to afford crude compound. The crude compound wastriturated with n-pentane to furnish 4.2 g (98%) of(2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octan-6-one(INT-37) as an off-white solid (˜1:1 mixture of stereoisomers). LCMS:calculated for [M+H]+=384.21, found 384.2.

Cis-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octan-6-one(INT-38) andtrans-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octan-6-one(INT-39)

The diastereomeric mixture of(2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octan-6-one(INT-37) (7.9 g) was separated by chiral SFC to afford 2.2 g ofcis-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octan-6-one(INT-38) as an off-white solid (HPLC peak-1) and 2.4 g oftrans-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octan-6-one(INT-39) as an off-white solid (HPLC peak-2). Preparative SFCConditions: column: Chiralpak AD-H (30×250 mm), 5μ; % co-solvent: 30.0%(100% Methanol); % CO₂: 70.0%; total flow: 90.0 g/min; back pressure:90.0 bar; UV: 214 nm; stack time: 6.3 min; load/inj: 74.0 mg; injectionsolvent: 200 mL methanol; No. of injections: 70; instrument details:Make/Model: SFC-200-003.

Cis-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octan-6-one(INT-38): ¹H NMR (DMSO-d₆): δ 7.38 (br s, 1H), 7.07 (br s, 2H),7.01-6.97 (m, 3H), 6.83 (d, J=6.8 Hz, 2H), 4.04 (s, 2H), 3.70 (s, 3H),2.66 (br s, 4H), 2.36 (br s, 2H), 1.82 (br s, 6H).

Trans-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7-diazaspiro[3.4]octan-6-one(INT-39): ¹H NMR (DMSO-d₆): δ 7.37-7.34 (m, 1H), 7.16 (d, J=6.8 Hz, 2H),7.08-7.05 (m, 1H), 6.91 (d, J=6.8 Hz, 2H), 6.83 (d, J=6.4 Hz, 2H), 6.77(s, 1H), 4.16 (s, 2H), 3.74 (s, 3H), 3.34 (s, 2H), 2.56 (d, J=1.0 Hz,2H), 2.26 (d, J=10.0 Hz, 2H), 1.88 (s, 6H).

General Scheme for the Synthesis of INT-43

Cis-5-(cyclopropylmethyl)-2-(dimethylamino)-7-(4-methoxybenzyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one(INT-42)

To a solution ofcis-2-dimethylamino-7-(4-methoxy-benzyl)-2-phenyl-5,7-diaza-spiro[3.4]octan-6-one(INT-40) (3.0 g, 8.22 mmol, 1.0 eq.) in dry DMF (160 ml) was added 60%NaH (657 mg, 16.438 mmol, 2 eq.) at 0° C. and the resulting mixture wasstirred for 30 min followed by addition of bromomethyl-cyclopropane (1.9ml, 20.54 mmol, 2.5 eq.) at 0° C. The reaction mixture was stirred at RTfor 16 h. The reaction mixture was quenched with ice-cold water (20 ml)and extracted with ethyl acetate (1 L). The organic layer was washedwith ice-cold water (3×100 ml), brine (250 ml) and dried over sodiumsulfate. Organic layer was concentrated under reduced pressure to getcrude product which was purified by column chromatography (silica gel;1.5% MeOH/DCM) to yieldcis-5-cyclopropylmethyl-2-dimethylamino-7-(4-methoxy-benzyl)-2-phenyl-5,7-diaza-spiro[3.4]octan-6-one(INT-42) as colourless sticky liquid. LCMS: calculated for [M+H]+=420.4,found 420.1.

Cis-5-cyclopropylmethyl-2-dimethylamino-2-phenyl-5,7-diaza-spiro[3.4]octan-6-one(INT-43)

To a stirred solution ofcis-5-cyclopropylmethyl-2-dimethylamino-7-(4-methoxy-benzyl)-2-phenyl-5,7-diaza-spiro[3.4]octan-6-one(INT-42) (2.0 g) in DCM (12 ml) was added TFA (12 ml) drop-wise at 0° C.The reaction mixture was stirred at RT for 16 h and then concentratedunder reduced pressure to get crude product which was purified by columnchromatography (silica gel neutralized by aqueous NH₃; 4% MeOH/DCM) toyieldcis-5-cyclopropylmethyl-2-dimethylamino-2-phenyl-5,7-diaza-spiro[3.4]octan-6-one(INT-43) as a white solid. Note: This step was done with another 1.0 gand 2.0 g batches. Combined yield: 60% (2.15 g, 7.18 mmol). LCMS:calculated for [M+H]+=300.3, found 300.2.

For further intermediates the synthesis in analogy to previouslydescribed methods is given in the following table. The syntheses of thebuilding blocks and intermediates have either been described previouslywithin this application or can be performed in analogy to the hereindescribed methods or by methods known to the person, skilled in the art.Such a person will also know which building blocks and intermediatesneed to be chosen for synthesis of each exemplary compound.

in analogy Inter- to m/z mediate Chemical Name Chemical Structure method[M + H]⁺ INT-17 tert-butyl trans-(7-(4-methoxybenzyl)-6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]octan-2-yl)(methyl) carbamate

INT-9  466.2 INT-18 tert-butyl trans-(5-(cyclobutylmethyl)-7-(4-methoxybenzyl)-6,8-dioxo-2-phenyl-5,7-diazaspiro[3.4]octan-2-yl)(methyl)carbamate

INT-10 534.3 INT-19 trans-5-(cyclobutylmethyl)-2-(methylamino)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione

INT-11 314.2 INT-20 trans-5-(cyclobutylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octane-6,8-dione

INT-12 328.2 INT-21 trans-5-(cyclobutylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one

INT-13 314.2 INT-22 trans-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one

INT-14 246.2 INT-23 trans-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetic acid tert-butyl ester

INT-15 360.2 INT-24 trans-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetic acid

INT-16 304.2 INT-26 cis-2-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetic acid

INT-16 372.2 INT-35 trans-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one

INT-34 264.15 INT-40 Cis-2-(dimethylamino)-7-(4-methoxybenzyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one

INT-38 366.2 INT-41 Trans-2-(dimethylamino)-7-(4-methoxybenzyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one

INT-39 366.2 INT-44 Cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-methoxybenzyl)-5,7- diazaspiro[3.4]octan-6-one

INT-42 438.3 INT-45 Cis--5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one

INT-43 318.2

Synthesis of Exemplary CompoundsCis-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetamide(SC-1)

To a solution of crudecis-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)aceticacid (INT-16) (120 mg, max. 0.196 mmol) in DCM (3.5 mL) were added Et₃N(0.137 mL, 0.98 mmol) and NH₄Cl (41.9 mg, 0.784 mmol) under a N₂atmosphere. HATU (112 mg, 0.294 mmol) was added and the mixture wasstirred at RT overnight. The mixture was diluted with MeOH (5 mL) andfiltered off. The residue was rinsed with MeOH (10 mL) and the combinedfiltrates were concentrated. The residue was purified by basicpreparative LC (HPLC instrument type: Agilent Technologies 1200preparative LC; column: Waters XSelect CSH (C18, 150×25 mm, 10μ); flow:43 mL/min; column temp: RT; eluent A: 99% acetonitrile+1% 10 mM ammoniumbicarbonate in water pH=9.0, eluent B: 10 mM ammonium bicarbonate inwater pH=9.0; lin. gradient: t=0 min 5% A, t=2.5 min 5% A, t=11 min 50%A, t=13 min 100% A, t=17 min 100% A; detection: DAD (210 nm)). Theproduct-containing fractions were concentrated to dryness andco-evaporated with MeCN (2×, 5 mL each) and Et₂O (2×, 5 mL each) toyieldcis-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetamide(SC-1) (42 mg, 0.139 mmol). LCMS: calculated for [M+H]⁺=303.2, found303.2. ¹H NMR (400 MHz, DMSO-d₆) δ 7.43-7.34 (m, 2H), 7.33-7.17 (m, 4H),6.98 (s, 1H), 6.89 (s, 1H), 3.45 (s, 2H), 2.85 (s, 2H), 2.75 (d, J=11.9Hz, 2H), 2.36 (d, J=11.9 Hz, 2H), 1.81 (s, 6H).

Cis-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one(SC-2)

To a solution ofcis-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)aceticacid (INT-16) (120 mg, max. 0.196 mmol) in DCM (3.5 mL) were added Et₃N(0.109 mL, 0.784 mmol) and thiomorpholine 1,1-dioxide (106 mg, 0.784mmol) under a N₂ atmosphere. HATU (112 mg, 0.294 mmol) was added and themixture was stirred at RT overnight. The mixture was diluted with MeOH(5 mL) and filtered off. The residue was rinsed with MeOH (10 mL) andthe combined filtrates were concentrated. The residue was purified bybasic preparative LC (HPLC instrument type: Agilent Technologies 1200preparative LC; column: Waters XSelect CSH (C18, 150×25 mm, 10); flow:43 mL/min; column temp: RT; eluent A: 99% acetonitrile+1% 10 mM ammoniumbicarbonate in water pH=9.0, eluent B: 10 mM ammonium bicarbonate inwater pH=9.0; lin. gradient: t=0 min 5% A, t=2.5 min 5% A, t=11 min 50%A, t=13 min 100% A, t=17 min 100% A; detection: DAD (210 nm)). Theproduct-containing fractions were concentrated to dryness andco-evaporated with MeCN (2×, 5 mL each) and Et₂O (2×, 5 mL each) toyieldcis-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one(SC-2) (52 mg, 0.124 mmol). LCMS: calculated for [M+H]⁺=421.2, found421.2. ¹H NMR (400 MHz, DMSO-d₆) δ 7.38 (t, J=7.5 Hz, 2H), 7.32-7.22 (m,3H), 6.99 (s, 1H), 3.86 (s, 2H), 3.79-3.66 (m, 4H), 3.18 (s, 2H), 3.02(s, 2H), 2.88 (s, 2H), 2.76 (d, J=11.9 Hz, 2H), 2.37 (d, J=11.9 Hz, 2H),1.80 (s, 6H).

Cis-5-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)-4-methoxypyrimidine-2-carbonitrile(SC-3)

This reaction was carried out under Ar. A mixture ofcis-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (INT-14)(83 mg, 0.338 mmol), 5-bromo-4-methoxypyrimidine-2-carbonitrile (80 mg,0.372 mmol), Cs₂CO₃ (331 mg, 1.015 mmol) and XantPhos (9.79 mg, 0.017mmol) in dry 1,4-dioxane (8 mL) was flushed with Ar for 5 min. Pd₂(dba)₃(31.0 mg, 0.034 mmol) was added and the reaction mixture was stirred at110° C. overnight. The reaction mixture was combined with a reactionmixture obtained from another experiment which started fromcis-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (INT-14)(41 mg, 0.167 mmol) using the described procedure. H₂O (10 mL) was addedand the aqueous layer was extracted with DCM (3×10 mL) and DCM/7 M NH₃in MeOH, 9:1 (3×10 mL). Organic layers were combined, dried (Na₂SO₄) andevaporated under reduced pressure. The product was subjected to flashchromatography (28 g silica, gradient DCM/(7 M NH₃ in MeOH), 1:0 to95:5). TLC-impure fractions were combined and subjected to flashchromatography again (28 g silica, gradient DCM/(7 M NH₃ in MeOH), 97:3to 95:5), to result in impure product which was triturated with MeOH(2×2 mL). This batch of product was combined with the TLC-pure batch ofthe first flash column. The resulting batch was triturated with MeOH(ca. 2 mL). The residue was dried in vacuo, to givecis-5-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)-4-methoxypyrimidine-2-carbonitrile(SC-3) (87 mg, 0.23 mmol, 46%). LCMS: calculated for [M+H]+=379.2, found379.2. ¹H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 7.37 (t, J=7.3 Hz, 2H),7.30 (t, J=7.3 Hz, 1H), 7.09 (d, J=7.2 Hz, 2H), 6.01 (s, 1H), 4.00 (s,3H), 3.76 (s, 2H), 2.71 (d, J=12.4 Hz, 2H), 2.63 (d, J=12.4 Hz, 2H),2.05 (s, 6H).

Cis-5-(cyclobutylmethyl)-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one(SC-6)

Step 1: 2-bromo-1-(1,1-dioxidothiomorpholino)ethanone

A solution of thiomorpholine 1,1-dioxide (1.0 g, 7.40 mmol) in DCM (30mL) was added dropwise over 20 min to a cooled (0° C.) and argon flushedmixture of 2-bromoacetyl bromide (970 μL, 11.10 mmol) and K₃PO₄ (3.93 g,18.5 mmol) in DCM (20 mL) and the mixture was stirred at RT overnight.The reaction mixture was diluted with DCM (50 mL) and quenched with aq.0.5 M HCl (10 mL). Water (50 mL) and brine (50 mL) were added and thelayers were separated. The aqueous layer was extracted with DCM (50 mL)and the combined organic layers were washed with aq. 10% KHCO₃ (100 mL)and brine (50 mL), dried over Na₂SO₄(s) and concentrated to dryness. Theresidue was triturated with Et₂O (50 mL) for 30 min. The solid materialwas filtered off, washed with some Et₂O and dried under reduced pressureto afford 2-bromo-1-(1,1-dioxidothiomorpholino)ethanone (1.20 g, 4.69mmol, 63%). LCMS: calculated for [M+H]⁺=256.1/258.1, found 256.0/258.0.

Step 2:cis-5-(cyclobutylmethyl)-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one(SC-6)

Oven dried glassware and an inert atmosphere (Ar(g)) were used. To asolution ofcis-5-(cyclobutylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one(INT-13) (40 mg, 0.128 mmol) in a mixture of dry DMF (2 mL) and dry THF(2 mL) was added 60% NaH in mineral oil (10.21 mg, 0.255 mmol) and themixture was stirred at RT. After 15 min gas evolution had ceased and asolution of 2-bromo-1-(1,1-dioxidothiomorpholino)ethanone (49.0 mg,0.191 mmol) in dry DMF (2 mL) was added dropwise. The mixture wasstirred at RT for 1 h. A mixture of brine/water (10 mL, 1/1, v/v) wascarefully added and the mixture was diluted with DCM (10 mL). The layerswere separated using a phase separator. The water layer was extractedwith DCM (4×5 mL). Organic layers were combined and concentrated invacuo (bath temperature 55° C.). The residue was concentratedconsequently from the solution in toluene, EtOAc and DCM to obtain acolourless sticky oil. The obtained crude product was purified by flashchromatography (4 g silica, gradient DCM/MeOH, 199:1 to 95:5) whichaffordedcis-5-(cyclobutylmethyl)-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one(SC-6) (47 mg, 0.096 mmol, 75%) as a white solid. LCMS: calculated for[M+H]⁺=489.6, found 489.3. ¹H NMR (400 MHz, CDCl₃) δ 7.38 (t, J=7.4 Hz,2H), 7.31 (d, J=7.2 Hz, 1H), 7.21 (d, J=7.2 Hz, 2H), 3.98 (broad d, 4H),3.89 (s, 2H), 3.32 (d, J=7.3 Hz, 2H), 2.99 (broad s, 4H), 2.93 (s, 2H),2.70-2.53 (m, 5H), 2.04 (m, 2H), 1.92 (s, 6H), 1.81 (m, 4H).

Trans-2-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetamide(SC-9)

To an ice-bath cooled suspension oftrans-5-(cyclobutylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one(INT-21) (378 mg, 1.21 mmol) in dry DMF (10 mL) under an argonatmosphere was added dry THF (10 mL) to give a clear solution. 60% NaHin mineral oil (72.4 mg, 1.81 mmol) was added and the mixture wasstirred at RT. After ˜20 min a solution of 2-chloroacetamide (201 μL,1.81 mmol) in dry THF (10 mL) was added dropwise and the mixture wasstirred at RT overnight. More 60% NaH in mineral oil (193 mg, 4.82 mmol)was added and the mixture was stirred at RT for 1 h, then2-chloroacetamide (201 μL, 1.81 mmol) was added. The mixture was stirredat RT for 3 h, quenched with water (50 mL) and extracted with EtOAc(2×75 mL). The combined organic layers were washed with brine (2×100mL), dried over Na₂SO₄(s) and concentrated to dryness. The crudematerial was purified by preparative LC (HPLC instrument type: AgilentTechnologies 1200 preparative LC; column: Waters XSelect CSH (C18,150×25 mm, 10 t); flow: 43 mL/min; column temp: RT; eluent A: 99%acetonitrile+1% 10 mM ammonium bicarbonate in water pH=9.0, eluent B: 10mM ammonium bicarbonate in water pH=9.0; lin. gradient: t=0 min 20% A,t=2.5 min 20% A, t=11 min 60% A, t=13 min 100% A, t=17 min 100% A;detection: DAD (210 nm)). Product-containing fractions were pooled,concentrated to dryness. The resulting product was concentrated againfrom the solution in Et₂O (2×5 mL) to affordtrans-2-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetamide(SC-9) (89 mg, 0.241 mmol, 20%). LCMS: calculated for [M+H]⁺=371.50,found: 371.3. ¹H NMR (400 MHz, DMSO-d₆) δ 7.37 (t, J=7.5 Hz, 2H), 7.31(s, 1H), 7.26 (t, J=7.2 Hz, 1H), 7.08 (d, J=7.6 Hz, 2H), 6.99 (s, 1H),3.65 (s, 2H), 3.59 (s, 2H), 2.88 (d, J=7.2 Hz, 2H), 2.58-2.46 (m, 2H),2.41 (d, J=12.8 Hz, 2H), 2.32 (dq, J=14.9, 7.4 Hz, 1H), 1.92 (s, 6H),1.86-1.76 (m, 2H), 1.68 (tt, J=19.5, 10.3 Hz, 2H), 1.51 (p, J=8.4 Hz,2H).

Cis-2-(Dimethylamino)-7-(4-methyl-2-morpholinopyrimidin-5-yl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one(SC-12)

K₂CO₃ (338 mg, 2.448 mmol) was added to a solution ofcis-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (INT-14)(200 mg, 0.816 mmol) and 4-(5-bromo-4-methylpyrimidin-2-yl)morpholine(314 mg, 1.224 mmol) in 1,4-dioxane (20 mL) at RT under argonatmosphere. To this reaction mixture, N,N-dimethylethylenediamine (71.8mg, 0.816 mmol) followed by CuI (155 mg, 0.816 mmol) were added anddegassed with argon for 15 minutes. The resulting reaction mixture wasthen maintained at 120° C. for 16 h. The reaction progress was checkedby LC-MS.

Following the above condition, another 200 mg of(2s,4s)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one wastreated with 4-(5-bromo-4-methylpyrimidin-2-yl)morpholine. Both theselots were mixed, quenched with water (30 mL) and extracted with ethylacetate (2×30 mL). The combined organic layer was concentrated underreduced pressure. The crude product was purified by prep-HPLC to afford37 mg (5%) ofcis-2-(dimethylamino)-7-(4-methyl-2-morpholinopyrimidin-5-yl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one(SC-12) as an off-white solid (TLC system: 10% MeOH in dichloromethane;Rf: 0.5). ¹H NMR (400 MHz, DMSO-d₆): δ 8.04 (s, 1H), 7.38-7.26 (m, 6H),3.65-3.60 (m, 8H), 3.10 (s, 2H), 2.86-2.82 (m, 2H), 2.46-2.41 (m, 2H),2.10 (s, 3H), 1.83 (s, 6H). Mass: m/z 423.2 (M+H) ion present.

Cis-7-(6-(azetidin-1-yl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one(SC-13)

Step 1: 2-(Azetidin-1-yl)-5-bromo-4-methylpyridine

Cs₂CO₃ (3.4 g, 10.526 mmol) was added to a stirred solution of2,5-dibromo-4-methylpyridine (1.0 g, 5.263 mmol) and azetidinehydrochloride (0.5 g, 5.263 mmol) in DMSO (10 mL) at RT. The resultingreaction mixture was heated to 90° C. and maintained under stirring for20 h. The reaction completion was monitored by TLC To the reactionmixture, water (30 mL) was added and extracted with ethyl acetate (2×30mL). The combined organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford 0.8 g (66%) of2-(azetidin-1-yl)-5-bromo-4-methylpyridine as a pale yellow solid. (TLCsystem: 30% ethyl acetate in pet-ether; Rf: 0.7).

Step 2:Cis-7-(6-(azetidin-1-yl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one(SC-13)

In analogy to the method described for SC-12cis-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one (INT-14)(200 mg, 0.816 mmol) was reacted with2-(azetidin-1-yl)-5-bromo-4-methylpyridine (278 mg, 1.224 mmol) to beconverted intocis-7-(6-(azetidin-1-yl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one(SC-13) (35 mg, 11%). ¹H NMR (400 MHz, zDMSO-d₆): δ 7.69 (s, 1H),7.38-7.33 (m, 2H), 7.31-7.23 (m, 3H), 7.14 (s, 1H), 6.14 (s, 1H),3.86-3.81 (m, 4H), 3.05 (s, 2H), 2.86-2.82 (m, 2H), 2.45-2.41 (m, 2H),2.29-2.21 (m, 2H), 1.98 (s, 3H), 1.83 (s, 6H). Mass: m/z 392.2 (M+H) ionpresent.

Cis-5-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methylpicolinonitrile(SC-15)

Step 1:cis-5-(2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methylpicolinonitrile(SC-14)

In analogy to the method described for SC-3cis-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one(INT-34) (120 mg, 0.456 mmol) was reacted with5-bromo-4-methyl-pyridine-2-carbonitrile (197 mg, 0.592 mmol) to beconverted intocis-5-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methylpicolinonitrile(SC-14) (133 mg, 77%). ¹H NMR (600 MHz, DMSO-d₆): δ 8.46 (s, 1H), 7.89(s, 1H), 7.66 (s, 1H), 7.41 (td, J=7.8, 6.0 Hz, 1H), 7.16-7.07 (m, 3H),2.92-2.86 (m, 2H), 2.51-2.45 (m, 2H), 2.19 (s, 3H), 1.86 (s, 6H). Mass:m/z 380.2 (M+H) ion present.

Step 2:cis-5-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methylpicolinonitrile(SC-15)

To a solution ofcis-5-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methylpicolinonitrile(SC-14) (60 mg, 0.158 mmol) in dry DMF (1.2 mL) under nitrogenatmosphere was added 60% NaH in mineral oil (9.5 mg, 0.237 mmol) and themixture was stirred at RT. After ˜5 min a solution ofbromomethylcyclopropane (23 μL, 0.237 mmol) was added. The reactionmixture was stirred at RT for 1.5 h, quenched with sat. aq. NH₄Cl (5 mL)and extracted with DCM (2×10 mL). The combined organic layers werewashed with brine, dried over Na₂SO₄(s) and concentrated to dryness. Thecrude material (75 mg) was purified by flash chromatography on silicagel (eluent DCM/MeOH gradient 0% to 6% methanol) to yield 40 mg (58%)cis-5-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methylpicolinonitrile(SC-15) as white solid. ¹H NMR (600 MHz, DMSO-d₆): δ 8.47 (s, 1H), 7.90(s, 1H), 7.42 (td, J=8.8, 8.3, 6.3 Hz, 1H), 7.16-7.08 (m, 3H), 3.43 (s,2H), 3.23 (d, J=6.6 Hz, 2H), 2.85-2.79 (m, 2H), 2.71-2.65 (m, 2H), 2.18(s, 3H), 1.88 (s, 6H), 1.13-1.03 (m, 1H), 0.56-0.47 (m, 2H), 0.39-0.31(m, 2H). Mass: m/z 434.2 (M+H) ion present.

Cis-7-(6-(difluoromethyl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one(SC-22)

Step 1: 5-bromo-2-(difluoromethyl)-4-methylpyridine

To the solution of 5-bromo-4-methyl-pyridine-2-carbaldehyde (200 mg,1.00 mmol) in DCM (7.7 mL) at −78° C. (diethylamino)sulfurtrifluoride(242 mg, 0.198 mL, 1.50 mmol) was added under nitrogen atmosphere. Thereaction mixture was allowed to warm up to RT over 4 h and stirred at RTovernight. The reaction mixture was quenched with 2 M aq. NaOH andextracted with DCM (3×). The combined organic layers were washed withbrine, dried over Na₂SO₄(s) and concentrated at 100 mbar. The resultingcrude product (220 mg) was used directly in the next step.

Step 2:cis-7-(6-(difluoromethyl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one(SC-22)

In analogy to the method described for SC-3cis-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one(INT-34) (200 mg, 0.760 mmol) was reacted with5-bromo-2-(difluoromethyl)-4-methylpyridine (219 mg, 0.987 mmol) to beconverted intocis-7-(6-(difluoromethyl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one(SC-22) (110 mg, 36%). ¹H NMR (600 MHz, DMSO-d₆): δ 8.38 (s, 1H), 7.54(s, 1H), 7.51 (s, 1H), 7.41 (td, J=8.0, 6.1 Hz, 1H), 7.23-7.03 (m, 3H),6.85 (t, J=55.0 Hz, 1H), 3.34 (s, 2H), 2.99-2.80 (m, 2H), 2.57-2.39 (m,2H), 2.20 (s, 3H), 1.86 (s, 6H). Mass: m/z 405.2 (M+H) ion present.

Cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(2-(methylsulfonyl)ethyl)-5,7-diazaspiro[3.4]octan-6-one(SC-31)

To the solution ofcis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one(INT-45) (80 mg, 0.252 mmol) in THF (2.1 mL) was added 1M potassiumtert-butylate in THF (0.378 mL, 0.378 mmol). The resulting mixture wasstirred 0.5h at RT, cooled to 0° C. and the solution of1-bromo-2-methylsulfonyl-ethane (71 mg, 0.378 mmol) in THF (1 mL) wasadded dropwise. The reaction mixture was stirred for 1h, quenched withwater and extracted with ethyl acetate (3×). The combined organic layerswere washed with brine, dried over Na₂SO₄(s) and concentrated todryness. Crude product (108 mg) was further purified by columnchromatography on silica gel (gradient 0 to 5% EtOH in DCM) to yield 53mg of semi-pure product which was further purified by reversed phaseHPLC to yield 28 mg (26%) ofcis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(2-(methylsulfonyl)ethyl)-5,7-diazaspiro[3.4]octan-6-one(SC-31) as a white solid. ¹H NMR (600 MHz, DMSO-d₆) δ 7.45 (td, J=8.0,6.2 Hz, 1H), 7.18-7.08 (m, 3H), 3.39 (s, 2H), 3.19 (t, J=6.9 Hz, 2H),3.10 (d, J=6.6 Hz, 2H), 2.94 (s, 2H), 2.91 (s, 3H), 2.68-2.62 (m, 2H),2.60-2.54 (m, 2H), 1.85 (s, 6H), 1.06-0.93 (m, 1H), 0.51-0.43 (m, 2H),0.34-0.26 (m, 2H). Mass: m/z 424.2 (M+H) ion present.

Cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(2-methoxy-2-methylpropyl)-5,7-diazaspiro[3.4]octan-6-one(SC-37)

Anhydrous NaOH powder (50.4 mg, 1.26 mmol) was suspended in anhydrousDMSO (5.25 mL) under nitrogen atmosphere and the resulting mixture wasstirred 40 min at RT.Cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one(INT-45) (100 mg, 0.315 mmol) and 1-bromo-2-methoxy-2-methylpropane (79mg, 0.473 mmol) were added. The resulting mixture was stirred 22h at 90°C. and a new portion of 1-bromo-2-methoxy-2-methylpropane (26.3 mg,0.158 mmol) was added. The reaction mixture was stirred for 4 h,quenched with brine (30 mL) and extracted with ethyl acetate (3×). Thecombined organic layers were dried over Na₂SO₄(s) and concentrated todryness. Crude product (152 mg) was purified by column chromatography onsilica gel (gradient 1 to 5% EtOH in DCM) to yield 78 mg (61%) ofcis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(2-methoxy-2-methylpropyl)-5,7-diazaspiro[3.4]octan-6-one(SC-37). ¹H NMR (600 MHz, DMSO-d₆): δ 7.48-7.41 (m, 1H), 7.17-7.11 (m,3H), 3.08 (d, J=6.5 Hz, 2H), 2.93 (s, 2H), 2.91 (s, 2H), 2.90 (s, 3H),2.64-2.59 (m, 2H), 2.56-2.50 (m, 3H), 1.86 (s, 6H), 1.04-0.97 (m, 1H),0.96 (s, 6H), 0.49-0.42 (m, 2H), 0.31-0.24 (m, 2H). Mass: m/z 404.3(M+H) ion present.

Cis-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-morpholinobenzyl)-5,7-diazaspiro[3.4]octan-6-one(SC-41)

To the solution ofcis-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one(INT-34) (100 mg, 0.380 mmol) in dioxane (15.2 mL) was added potassiumtert-butylate (93.8 mg, 0.836 mmol) and the resulting mixture wasstirred 10 min at RT. 4-[4-(Chloromethyl)phenyl]morpholine hydrochloride(104 mg, 0.418 mmol) was added and the reaction mixture was stirred atRT for 3h. A new portion of potassium tert-butylate (42.6 mg, 0.380mmol) was added. The reaction mixture was stirred further 19h at RT andconcentrated to dryness. The solid residue was taken up in water (10mL)/ethyl acetate (20 mL), organic phase separated and aqueous phaseextracted with ethyl acetate (20 mL). The combined organic layers werewashed with brine, dried over Na₂SO₄(s) and concentrated to dryness.Crude product (158 mg) was further purified by column chromatography onsilica gel (gradient 0 to 7% (0.5M NH₃ in MeOH) in DCM) to yield 46 mgof semi-pure product which was further purified by reversed phase HPLCto yield 27 mg (16%) ofcis-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-morpholinobenzyl)-5,7-diazaspiro[3.4]octan-6-one(SC-41) as a white solid. ¹H NMR (600 MHz, DMSO-d₆): δ 7.38 (td, J=7.6,5.9 Hz, 1H), 7.12-7.03 (m, 3H), 6.95 (d, J=8.3 Hz, 3H), 6.87-6.81 (m,2H), 4.02 (s, 2H), 3.74-3.69 (m, 4H), 3.08-3.03 (m, 4H), 2.70-2.65 (m,4H), 2.39-2.33 (m, 2H), 1.81 (s, 6H). Mass: m/z 439.3 (M+H) ion present.

Cis-3-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)propanenitrile(SC-44)

To the solution ofcis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one(INT-45) (130 mg, 0.410 mmol) in DMSO (1.7 mL) was added potassiumtert-butylate (68.9 mg, 0.614 mmol) at RT under nitrogen atmosphere. Theresulting mixture was stirred 15 min at RT. 3-Bromopropionitrile (51 μL,0.614 mmol) in DMSO (1.7 mL) was added dropwise and the reaction mixturewas stirred at RT for 18h. A new portion of 3-bromopropionitrile (17 μL,0.205 mmol) was added. The reaction mixture was stirred further 6h atRT, quenched with brine (30 mL) and extracted with ethyl acetate (3×).The combined organic layers were dried over Na₂SO₄(s) and concentratedto dryness. Crude product (208 mg) was further purified by columnchromatography on silica gel (gradient 2 to 5% EtOH in DCM) to yield 105mg (87%) ofcis-3-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)propanenitrile(SC-44) as a white solid. ¹H NMR (600 MHz, DMSO-d₆+TFA): δ 7.68-7.54 (m,3H), 7.41 (td, J=8.5, 2.5 Hz, 1H), 3.24 (d, J=6.7 Hz, 2H), 3.21 (t,J=6.5 Hz, 2H), 3.07-3.02 (m, 2H), 3.01-2.96 (m, 2H), 2.85 (s, 2H),2.56-2.52 (m, 8H), 1.12-0.99 (m, 1H), 0.47-0.39 (m, 2H), 0.38-0.30 (m,2H). Mass: m/z 371.2 (M+H) ion present.

The following compounds were prepared in analogy and by combiningpreviously described methods:

Reac- in analogy m/z Example Chemical name Chemical structure tant IReactant II to method ¹H NMR data (M + H)⁺ SC-4 trans-2-(dimethylamino)-7-(2- (1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7- diazaspiro[3.4]octan-6-one

INT-24 thiomorpholine 1,1-dioxide SC-2 ¹H NMR (400 MHz, DMSO-d6) δ 7.34(t, J = 7.5 Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H), 7.03 (d, J = 7.3 Hz, 2H),6.77 (s, 1H), 4.01 (s, 2H), 3.90- 3.77 (m, 4H), 3.63 (s, 2H), 3.28 (s,2H), 3.11 (s, 2H), 2.65 (d, J = 12.3 Hz, 2H), 2.29 (d, J = 12.2 Hz, 2H),1.93 (s, 6H). 421.2 SC-5  trans-5-(2-(dimethylamino)-6-oxo-2-phenyl-5,7- diazaspiro[3.4]octan-7-yl)-4- methoxypyrimidine-2-carbonitrile

INT-22 5-bromo-4- methoxypyrimi- dine-2- carbonitrile SC-3 ¹H NMR (400MHz, DMSO-d6) δ 8.79 (s, 1H), 7.71 (s, 1H), 7.36 (t, J = 7.5 Hz, 2H),7.26 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 7.1 Hz, 2H), 4.13 (s, 2H), 4.06(s, 3H), 2.75 (dd, J = 10.1, 2.6 Hz, 2H), 2.42-2.34 (m, 2H), 1.95 (s,6H). 379.2 SC-7  trans-5-(cyclobutylmethyl)-2-(dimethylamino)-7-(2-(1,1- dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7- diazaspiro[3.4]octan-6-one

INT-21 2-bromo-1-(1,1- dioxidothiomor- pholino)etha-none SC-6 ¹H NMR(400 MHz, DMSO-d₆) δ 7.37 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7.3 Hz, 1H),7.08 (d, J = 7.3 Hz, 2H), 4.06 (s, 2H), 3.84 (s, 4H), 3.62 (s, 2H), 3.28(m, 2H), 3.11 (m, 2H), 2.89 (d, J = 7.2 Hz, 2H), 2.55 (m, 2H), 2.41 (d,J = 12.8 Hz, 2H), 2.33 (m, 1H), 1.92 (s, 6H), 1.86-1.76 (m, 2H), 1.68(m, 2H), 1.53 (m, 2H). 489.3 SC-8  cis-2-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2- phenyl-5,7- diazaspiro[3.4]octan-7-yl)acetamide

INT-26 ammonium chloride SC-1 ¹H-NMR (400 MHz, CDCl3) δ 7.38 (m, 2H),7.35-7.29 (m, 1H), 7.23- 7.17 (m, 2H), 6.25 (bs, 1H), 5.21 (bs, 1H),3.64 (s, 2H), 3.33 (d, J = 7.3 Hz, 2H), 2.85 (s, 2H), 2.69- 2.51 (m,5H), 2.04 (m, 2H), 1.94 (s, 6H), 1.89-1.73 (m, 4H). 371.3 SC-10cis-5-(5-(cyclobutylmethyl)-2- (dimethylamino)-6-oxo-2- phenyl-5,7-diazaspiro[3.4]octan-7-yl)-4- methoxypyrimidine-2- carbonitrile

INT-13 5-bromo-4- methoxypyrimi- dine-2- carbonitrile SC-3 ¹H NMR (400MHz, CDCl₃) δ 8.85 (s, 1H), 7.41 (m, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.24(m, 2H) 3.85 (s, 3H), 3.42 (d, J = 7.3 Hz, 2H), 3.36 (s, 2H), 2.78-2.70(m, 2H), 2.67 (m, 1H), 2.63-2.59 (m, 2H), 2.12- 2.03 (m, 2H), 1.97 (s,6H), 1.85 (m, 4H). 447.3 SC-11 trans-5-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2- phenyl-5,7- diazaspiro[3.4]octan-7-yl)-4-methoxypyrimidine-2- carbonitrile

INT-21 5-bromo-4- methoxypyrimi- dine-2- carbonitrile SC-3 ¹H NMR (400MHz, CDCl₃) δ 8.87 (s, 1H), 7.39 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.3Hz, 1H), 7.11-7.00 (m, 2H), 4.16 (s, 2H), 4.10 (s, 3H), 3.07 (d, J = 7.2Hz, 2H), 2.65- 2.54 (m, 4H), 2.46 (m, 1H), 2.02 (s, 6H), 1.92 (ddt, J =11.3, 8.2, 3.4 Hz, 2H), 1.76 (tdd, J = 14.6, 8.6, 2.7 Hz, 2H), 1.68-1.58(m, 2H). 447.3 SC-16 Cis-6-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3- fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-5- methylnicotinonitrile

INT-34 6-bromo-5- methyl-pyridine- 3-carbonitrile (step 1);bromomethylcyclo- propane (step 2) SC-15 ¹H NMR (600 MHz, DMSO-d6) δ8.56 (d, J = 2.2 Hz, 1H), 8.13-8.09 (m, 1H), 7.44 (td, J = 8.0, 6.2 Hz,1H), 7.14 (ddd, J = 16.1, 7.8, 2.7 Hz, 3H), 3.45 (s, 2H), 3.22 (d, J =6.7 Hz, 2H), 2.89-2.83 (m, 2H), 2.69-2.62 (m, 2H), 2.24 (s, 3H), 1.88(s, 6H), 1.10-1.03 (m, 1H), 0.54-0.46 (m, 2H), 0.38-0.29 (m, 2H). 434.2SC-17 Cis-2-(dimethylamino)-2-(3- fluorophenyl)-7-(5-(trifluoromethoxy)pyridin-2- yl)-5,7-diazaspiro[3.4]octan-6- one

INT-34 2-bromo-5- (trifluoromethoxy) pyridine SC-3 ¹H NMR (600 MHz,DMSO-d₆) δ 8.25-8.18 (m, 2H), 7.93 (s, 1H), 7.76 (dd, J = 9.5, 3.0 Hz,1H), 7.47 (td, J = 7.9, 6.2 Hz, 1H), 7.22- 7.13 (m, 3H), 3.50 (s, 2H),2.91- 2.85 (m, 2H), 2.49-2.43 (m, 2H), 1.84 (s, 6H). 425.2 SC-18Cis-5-(cyclopropylmethyl)-2- (dimethylamino)-2-(3- fluorophenyl)-7-(5-(trifluoromethoxy)pyridin-2- yl)-5,7-diazaspiro[3.4]octan-6- one

SC-17 bromomethylcyclo- propane SC-15 (step 2) ¹H NMR (600 MHz, DMSO-d6)δ 8.26-8.18 (m, 2H), 7.79 (ddd, J = 9.3, 2.9, 1.1 Hz, 1H), 7.48 (td, J =8.0, 6.3 Hz, 1H), 7.23-7.14 (m, 3H), 3.54 (s, 2H), 3.25 (d, J = 6.6 Hz,2H), 2.84-2.77 (m, 2H), 2.69- 2.63 (m, 2H), 1.87 (s, 6H), 1.15- 1.00 (m,1H), 0.56-0.48 (m, 2H), 0.41-0.33 (m, 2H). 479.2 SC-19Cis-2-(dimethylamino)-7-(4- methyl-6-morpholinopyridin-3-yl)-2-phenyl-5,7- diazaspiro[3.4]octan-6-one

INT-14 (step 2) 5-bromo-2-fluoro- 4-methylpyridine, morpholine (step 1)SC-13 ¹H NMR (DMSO-d6): δ 7.78 (s, 1H), 7.39-7.31 (m, 2H), 7.32-7.27 (m,2H), 7.26-7.24 (m, 1H), 7.19 (s, 1H), 6.62 (s, 1H), 3.65-3.62 (m, 4H),3.38-3.36 (m, 4H), 3.07 (s, 2H), 2.85-81 (m, 2H), 2.45-2.41 (m, 2H),2.01 (s, 3H), 1.84 (s, 6H). 422.3 SC-20 Cis-2-(dimethylamino)-7-(6-(2-hydroxypropan-2-yl)-4- methylpyridin-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one

INT-14 2-(5-bromo-4- methylpyridin-2- yl)propan-2-ol SC-12 ¹H NMR(DMSO-d₆): δ 8.13 (s, 1H), 7.44 (s, 1H), 7.37-7.24 (m, 6H), 5.13 (bs,1H), 3.17(s, 2H), 2.87 (d, 2H), 2.46 (d, 2H), 2.10 (s, 3H), 1.84 (s,6H), 1.36 (s, 6H). 395.3 SC-21 Cis-2-(dimethylamino)-7-(4-(2-hydroxypropan-2-yl)-2- methylphenyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one

INT-14 2-(4-bromo-3- methylphenyl) propan-2-ol SC-12 ¹H NMR (DMSO-d₆): δ7.37-7.32 (m, 2H), 7.31-7.28 (m, 2H), 7.27- 7.22 (m, 2H), 7.18-7.11 (m,2H), 6.95-6.92 (m, 1H), 4.91 (s, 1H), 3.08 (s, 2H), 2.86-2.84 (m, 2H),2.45-2.43 (m, 2H), 2.06 (s, 3H), 1.84 (s, 6H), 1.35 (s, 6H). 394.2 SC-23Cis--2-(dimethylamino)-5- ((3-fluorooxetan-3-yl)methyl)-2-(3-fluorophenyl)-7-(5- (trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6- one

SC-17 (3-fluorooxetan- 3-yl)methyl 4- methylbenzene- sulfonate SC-15(step 2) ¹H NMR (600 MHz, DMSO-d₆) δ 8.26 (d, J = 2.9 Hz, 1H), 8.20 (d,J = 9.3 Hz, 1H), 7.87-7.77 (m, 1H), 7.47 (td, J = 7.8, 6.0 Hz, 1H),7.24- 7.12 (m, 3H), 4.86-4.74 (m, 2H), 4.64 (dd, J = 20.8, 8.1 Hz, 2H),3.91 (d, J = 21.4 Hz, 2H), 3.54 (s, 2H), 2.84-2.75 (m, 2H), 2.63 2.51(m, 2H), 1.84 (s, 6H). 513.2 SC-24 Cis-5-(cyclopropylmethyl)-7-(6-(difluoromethyl)-4- methylpyridin-3-yl)-2- (dimethylamino)-2-(3-fluorophenyl)-5,7- diazaspiro[3.4]octan-6-one

SC-22 bromomethylcyclo- propane SC-15 (step 2) ¹H NMR (600 MHz, DMSO-d₆)δ 8.40 (s, 1H), 7.56 (s, 1H), 7.45 7.36 (m, 1H), 7.23-7.03 (m, 3H), 6.87(t, J = 55.0 Hz, 1H), 3.22 (d, J = 6.6 Hz, 2H), 2.98-2.74 (m, 2H),2.82-2.60 (m, 2H), 2.20 (s, 3H), 1.89 (s, 6H), 1.16-1.04 (m, 1H), 0.53(dtd, J = 8.3, 4.1, 1.9 Hz, 2H), 0.34 (dd, J = 4.8, 1.7 Hz, 2H). 459.2SC-25 Cis-2-(dimethylamino)-7-(2- morpholinopyrimidin-5-yl)-2-phenyl-5,7- diazaspiro[3.4]octan-6-one

INT-14 4-(5- bromopyrimidin- 2-yl)morpholine SC-12 ¹H NMR (DMSO-d₆): δ8.31 (s, 2H), 7.54 (s, 1H), 7.40-7.37 (m, 2H), 7.31-7.28 (m, 3H),3.62-3.60 (m, 4H), 3.57-3.55 (m, 4H), 3.29 (s, 2H), 2.85-2.82 (m, 2H),2.48-2.44 (m, 2H), 1.83 (s, 6H). 409.3 SC-26Cis-2-(dimethylamino)-5-((1- fluorocyclopropyl)methyl)-2-(3-fluorophenyl)-7-(5- (trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6- one

SC-17 (1- fluorocyclopropyl) methyl 4- methylbenzene- sulfonate SC-15(step 2) ¹H NMR (600 MHz, DMSO-d₆): δ 8.26 (d, J = 2.9 Hz, 1H), 8.20 (d,J = 9.3 Hz, 1H), 7.81 (ddd, J = 9.3, 2.9, 1.1 Hz, 1H), 7.48 (td, J =7.7, 6.0 Hz, 1H), 7.19 (dd, J = 9.9, 8.0 Hz, 3H), 3.79 (d, J = 20.6 Hz,2H), 3.58 (s, 2H), 2.86-2.77 (m, 2H), 2.77-2.66 (m, 2H), 1.87 (s, 6H),1.10-1.00 (m, 2H), 0.98-0.86 (m, 2H). 497.2 SC-27Cis-2-(dimethylamino)-2-(3- fluorophenyl)-5-((1-hydroxycyclobutyl)methyl)-7- (5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan- 6-one

SC-17 [1-[tert- butyl(dimethyl) silyl]oxycyclobutyl] methyl 4-methylbenzene- sulfonate SC-15 (step 2) ¹H NMR (600 MHz, DMSO-d₆): δ8.25 (d, J = 2.9 Hz, 1H), 8.21 (d, J = 9.3 Hz, 1H), 7.82-7.76 (m, 1H),7.47 (td, J = 8.0, 6.3 Hz, 1H), 7.17 (dddt, J = 10.5, 5.7, 4.3, 1.9 Hz,3H), 3.50 (s, 2H), 3.44 (s, 2H), 2.79- 2.69 (m, 4H), 2.16 (tt, J = 8.7,3.1 Hz, 2H), 1.91 (qd, J = 9.4, 2.7 Hz, 2H), 1.84 (s, 6H), 1.72-1.62 (m,1H), 1.60-1.51 (m, 1H). 509.2 SC-28 Cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3- fluorophenyl)-7-(4-(2- hydroxypropan-2-yl)phenyl)-5,7-diazaspiro[3.4]octan-6-one

INT-34 2-(4-bromo-3- methylphenyl) propan-2-ol (step 1);bromomethylcyclo- propane (step 2) SC-15 ¹H NMR (600 MHz, DMSO-d₆) δ7.46 (td, J = 8.1, 6.2 Hz, 1H), 7.34- 7.28 (m, 2H), 7.22-7.19 (m, 2H),7.19-7.12 (m, 3H), 4.88 (d, J = 0.8 Hz, 1H), 3.36 (s, 2H), 3.22 (d, J =6.6 Hz, 2H), 2.80-2.72 (m, 2H), 2.69-2.63 (m, 2H), 1.88 (s, 6H), 1.36(s, 6H), 1.08 (ddt, J = 9.7, 8.0, 3.1 Hz, 1H), 0.54-0.46 (m, 2H),0.38-0.30 (m, 2H). 452.3 SC-29 Cis-2-(dimethylamino)-5-((3-fluorooxetan-3-yl)methyl)-2- phenyl-7-(5- (trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6- one

INT-14 2-bromo-5- (trifluoromethoxy) pyridine (step 1); (3-fluorooxetan-3-yl)methyl 4- methylbenzene- sulfonate (step 2) SC-15 ¹H NMR (600 MHz,DMSO-d₆) δ 8.25 (d, J = 2.9 Hz, 1H), 8.19 (d, J = 9.2 Hz, 1H), 7.82 (dd,J = 9.2, 2.9 Hz, 1H), 7.43 (t, J = 7.5 Hz, 2H), 7.40-7.29 (m, 3H), 4.80(ddd, J = 21.7, 7.9, 1.3 Hz, 2H), 4.64 (dd, J = 20.8, 8.1 Hz, 2H), 3.91(d, J = 21.3 Hz, 2H), 3.51 (s, 2H), 2.84-2.74 (m, 2H), 2.63-2.51 (m,2H), 1.83 (s, 6H). 495.2 SC-30 Cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3- fluorophenyl)-7-((6- (trifluoromethyl)pyridin-3-yl)methyl)-5,7- diazaspiro[3.4]octan-6-one

INT-45 5-(Chloromethyl)- 2- (trifluoromethyl) pyridine SC-15 (step 2) ¹HNMR (400 MHz, DMSO-d₆): δ 8.53 (d, J = 1.9 Hz, 1H), 7.88- 7.77 (m, 2H),7.39 (q, J = 7.6, 7.1 Hz, 1H), 7.14-7.04 (m, 3H), 4.31 (s, 2H), 3.14 (d,J = 6.5 Hz, 2H), 2.82 (s, 2H), 2.67-2.54 (m, 4H), 1.83 (s, 6H),1.10-0.99 (m, 1H), 0.54-0.43 (m, 2H), 0.37-0.26 (m, 2H). 477.2 SC-32Cis-5-(cyclopropylmethyl)-2- (dimethylamino)-2-phenyl-7-(5-(trifluoromethoxy)pyridin- 2-yl)-5,7-diazaspiro[3.4]octan- 6-one

INT-14 2-bromo-5- (trifluoromethoxy) pyridine (step 1);bromomethylcyclo- propane (step 2) SC-15 ¹H NMR (600 MHz, DMSO-d₆) δ8.24-8.19 (m, 2H), 7.81-7.76 (m, 1H), 7.44 (t, J = 7.6 Hz, 2H),7.38-7.32 (m, 3H), 3.51 (s, 2H), 3.25 (d, J = 6.7 Hz, 2H), 2.84- 2.78(m, 2H), 2.69-2.64 (m, 2H), 1.85 (s, 6H), 1.10 (ddt, J = 9.7, 8.1, 3.2Hz, 1H), 0.53 (dt, J = 10.3, 2.9 Hz, 2H), 0.41-0.33 (m, 2H). 461.2 SC-33Cis-5-(cyclopropylmethyl)-2- (dimethylamino)-7-((3-fluorooxetan-3-yl)methyl)-2- (3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one

INT-45 (3-fluorooxetan- 3-yl)methyl 4- methylbenzene- sulfonate SC-15(step 2) ¹H NMR (600 MHz, DMSO-d₆) δ 7.44 (q, J = 7.4 Hz, 1H), 7.19-7.07 (m, 3H), 4.48 (ddd, J = 44.0, 20.0, 7.9 Hz, 4H), 3.49 (d, J = 23.3Hz, 2H), 3.11 (d, J = 6.6 Hz, 2H), 2.90 (s, 2H), 2.68-2.60 (m, 2H),2.60-2.52 (m, 2H), 1.85 (s, 6H), 1.08-0.95 (m, 1H), 0.53-0.41 (m, 2H),0.36-0.24 (m, 2H). 406.2 SC-34 Cis-5-(cyclopropylmethyl)-7-(6-cyclopropylpyridin-3-yl)-2- (dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one

INT-14 5-Bromo-2- cyclopropylpyridine (step 1); bromomethylcyclo-propane (step 2) SC-15 ¹H NMR (600 MHz, DMSO-d₆) δ 8.26 (d, J = 2.6 Hz,1H), 7.60 (dt, J = 8.5, 2.1 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.36-7.28(m, 3H), 7.14 (d, J = 8.6 Hz, 1H), 3.36 (s, 2H), 3.25 (d, J = 6.7 Hz,2H), 2.82 2.76 (m, 2H), 2.71-2.65 (m, 2H), 2.02-1.94 (m, 1H), 1.87 (s,6H), 1.17-1.02 (m, 1H), 0.88-0.82 (m, 2H), 0.78 (dq, J = 6.8, 4.1, 3.6Hz, 2H), 0.51 (dt, J = 8.3, 3.0 Hz, 2H), 0.39-0.31 (m, 2H). 417.3 SC-35Cis-7-(6-cyclopropyl-4- methylpyridin-3-yl)-5- (cyclopropylmethyl)-2-(dimethylamino)-2-phenyl- 5,7-diazaspiro[3.4]octan-6-one

INT-14 5-bromo-2- cyclopropyl-4- methylpyridine (step 1),bromomethylcyclo- propane (step 2) SC-12 for step 1; SC- 15 (step 2) forstep 2 ¹H NMR (600 MHz, DMSO-d₆) δ 8.05 (s, 1H), 7.37 (t, J = 7.6 Hz,2H), 7.33-7.26 (m, 2H), 7.29 7.24 (m, 1H), 7.10 (d, J = 1.1 Hz, 1H),3.20 (d, J = 6.5 Hz, 2H), 3.17 (s, 2H), 2.82-2.76 (m, 2H), 2.69- 2.63(m, 2H), 2.05 (s, 3H), 1.99 (tt, J = 8.2, 4.8 Hz, 1H), 1.87 (s, 6H),1.08 (ddt, J = 9.7, 8.0, 3.2 Hz, 1H), 0.87 (dt, J = 8.1, 3.0 Hz, 2H),0.83- 0.80 (m, 2H), 0.54-0.47 (m, 2H), 0.37-0.30 (m, 2H). 431.3 SC-36Cis-7-(6-cyclopropyl-4- methylpyridin-3-yl)-2- (dimethylamino)-5-((3-fluorooxetan-3-yl)methyl)-2- phenyl-5,7- diazaspiro[3.4]octan-6-one

INT-14 5-bromo-2- cyclopropyl-4- methylpyridine (step 1), (3-fluorooxetan-3- yl)methyl 4- methylbenzene- sulfonate (step 2) SC-12 forstep 1; SC- 15 (step 2) for step 2 ¹H NMR (600 MHz, DMSO-d₆) δ 8.07 (s,1H), 7.37 (t, J = 7.6 Hz, 2H), 7.337.22 (m, 3H), 7.12 (s, 1H), 4.82-4.70(m, 2H), 4.63 (dd, J = 20.6, 8.0 Hz, 2H), 3.85 (d, J = 22.0 Hz, 2H),3.19 (s, 2H), 2.84 2.74 (m, 2H), 2.64-2.55 (m, 2H), 2.05 (s, 3H), 2.00(tt, J = 8.2, 4.8 Hz, 1H), 1.85 (s, 6H), 0.92-0.86 (m, 2H), 0.84-0.79(m, 2H). 465.3 SC-38 Cis-2-(dimethylamino)-2- phenyl-7-(2-pyridin-4-ylpyrimidin-5-yl)-5,7- diazaspiro[3.4]octan-6-one

INT-14 5-bromo-2-(4- pyridyl)pyrimidine SC-12 ¹H NMR (600 MHz, DMSO-d₆ +TFA): δ 10.59 (s, 1H), 9.01-8.96 (m, 3H), 8.72 (d, J = 6.9 Hz, 2H), 8.08(s, 1H), 7.69 (dd, J = 6.6, 2.9 Hz, 2H), 7.57 (dd, J = 5.0, 1.8 Hz, 3H),3.303.24 (m, 2H), 3.10- 3.05 (m, 2H), 2.52 (s, 6H). 401.2 SC-39Cis-5-(cyclopropylmethyl)-2- (dimethylamino)-2-phenyl-7-[5-(trifluoromethyl)pyridin-3- yl]-5,7-diazaspiro[3.4]octan-6- one

INT-43 3-Bromo-5- trifluoromethyl- pyridine SC-12 ¹H NMR (600 MHz,DMSO-d₆) δ 8.67 (d, J = 2.5 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.25 (t,J = 2.3 Hz, 1H), 7.43 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H),7.32-7.27 (m, 2H), 3.59 (s, 2H), 3.32 (d, J = 6.7 Hz, 2H), 2.85-2.80 (m,2H), 2.77 2.71 (m, 2H), 1.88 (s, 6H), 1.18- 1.09 (m, 1H), 0.53 (dt, J =8.2, 3.0 Hz, 2H), 0.41-0.34 (m, 2H). 445.2 SC-40Cis-5-[5-(cyclopropylmethyl)- 2-(dimethylamino)-6-oxo-2- phenyl-5,7-diazaspiro[3.4]octan-7-yl]-3- (trifluoromethyl)pyridine-2- carbonitrile

INT-43 5-Bromo-2- cyano-3- (trifluoromethyl) pyridine SC-12 ¹H NMR (600MHz, DMSO-d₆): δ 8.81 (d, J = 2.4 Hz, 1H), 8.43 (d, J = 2.5 Hz, 1H),7.43 (t, J = 7.6 Hz, 2H), 7.37-7.31 (m, 1H), 7.30- 7.25 (m, 2H), 3.71(s, 2H), 3.37 (d, J = 6.7 Hz, 2H), 2.83 (d, J = 13.7 Hz, 2H), 2.78 (d, J= 13.5 Hz, 2H), 1.88 (s, 6H), 1.20-1.11 (m, 1H), 0.54 (dt, J = 8.2, 3.0Hz, 2H), 0.43- 0.33 (m, 2H). 470.2 SC-42 Cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3- fluorophenyl)-7-[(1- hydroxycyclobutyl)methyl]-5,7-diazaspiro[3.4]octan-6-one

INT-45 [1-[tert- butyl(dimethyl) silyl]oxycyclobutyl] methyl 4-methylbenzene- sulfonate SC-37 ¹H NMR (600 MHz, DMSO-d₆): δ 7.46 (q, J =7.3 Hz, 1H), 7.17 (s, 3H), 3.11 (d, J = 6.5 Hz, 2H), 3.02 (s, 2H), 2.99(s, 2H), 2.77-2.57 (m, 4H), 2.01-1.86 (br s, 6H), 1.86-1.74 (m, 4H),1.59-1.51 (m, 1H), 1.42-1.32 (m, 1H), 1.06- 0.98 (m, 1H), 0.50-0.43 (m,2H), 0.33-0.26 (m, 2H). 402.3 SC-43 Cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-7- (2-pyridin-4-ylpyrimidin-5-yl)-5,7-diazaspiro[3.4]octan-6- one

SC-38 bromomethylcyclo- propane SC-15 (step 2) ¹H NMR (600 MHz, DMSO-d₆)δ 8.94 (s, 2H), 8.72-8.68 (m, 2H), 8.17-8.13 (m, 2H), 7.44 (t, J = 7.5Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.31 (d, J = 7.5 Hz, 2H), 3.60 (s,2H), 2.84 (d, J = 13.7 Hz, 2H), 2.76 (d, J = 13.6 Hz, 2H), 1.88 (s, 6H),1.20-1.08 (m, 1H), 0.58-0.50 (m, 2H), 0.43-0.35 (m, 2H). One CH₂ signaloverlaps with residual water peak (observed in HSQC: (3.3; 44.8)). 455.3SC-45 Cis-3-[5-(cyclopropylmethyl)- 2-(dimethylamino)-6-oxo-2-phenyl-5,7- diazaspiro[3.4]octan-7- yl]propanenitrile

INT-43 3- Bromopropionitrile SC-44 ¹H NMR (600 MHz, DMSO-d₆) δ 7.40 (t,J = 7.6 Hz, 2H), 7.34-7.27 (m, 3H), 3.21 (t, J = 6.6 Hz, 2H), 3.12 (d, J= 6.6 Hz, 2H), 2.92 (s, 2H), 2.67 (d, J = 13.2 Hz, 2H), 2.60 (d, J =13.1 Hz, 2H), 2.56 (t, J = 6.5 Hz, 2H), 1.84 (s, 6H), 1.06-0.99 (m, 1H),0.52-0.44 (m, 2H), 0.34- 0.27 (m, 2H). 353.2 SC-46Cis-5-(cyclopropylmethyl)-2- (dimethylamino)-7-[(1-hydroxycyclobutyl)methyl]-2- phenyl-5,7- diazaspiro[3.4]octan-6-one

INT-43 [1-[tert- butyl(dimethyl) silyl]oxycyclobutyl] methyl 4-methylbenzene- sulfonate SC-37 ¹H NMR (600 MHz, DMSO-d₆): δ 7.39 (t, J =7.6 Hz, 2H), 7.32-7.25 (m, 3H), 3.10 (d, J = 6.6 Hz, 2H), 3.01 (s, 2H),2.98 (s, 2H), 2.65- 2.59 (m, 2H), 2.59-2.53 (m, 2H), 1.86-1.80 (m, 8H),1.77 (qd, J = 9.4, 2.5 Hz, 2H), 1.59-1.52 (m, 1H), 1.36 (dp, J = 11.3,8.9 Hz, 1H), 1.06-0.98 (m, 1H), 0.47 (dt, J = 10.1, 2.9 Hz, 2H),0.33-0.26 (m, 2H). 384.3 SC-47 Cis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3- fluorophenyl)-7-[2-(oxetan-3- yl)ethyl]-5,7-diazaspiro[3.4]octan-6-one

INT-45 2-(oxetan-3- yl)ethyl 4- methylbenzene- sulfonate SC-44 ¹H NMR(600 MHz, DMSO-d₆): δ 7.49-7.41 (m, 1H), 7.18-7.11 (m, 3H), 4.54 (dd, J= 7.8, 5.8 Hz, 2H), 4.17 (t, J = 6.1 Hz, 2H), 3.08 (d, J = 6.5 Hz, 2H),2.89 (t, J = 6.9 Hz, 2H), 2.82 (s, 2H), 2.85-2.76 (m, 1H), 2.67-2.61 (m,2H), 2.59- 2.53 (m, 2H), 1.85 (s, 6H), 1.62 (q, J = 7.2 Hz, 2H),1.04-0.97 (m, 1H), 0.47 (dt, J = 10.4, 3.0 Hz, 2H), 0.31-0.25 (m, 2H).402.3

Names and structures of exemplified compounds:

Pharmacological Investigations

Functional investigation on the human mu-opioid receptor (hMOP), humankappa-opioid receptor (hKOP), human delta-opioid receptor (hDOP), andhuman nociceptin/orphanin FQ peptide receptor (hNOP)

Human Mu-Opioid Peptide (hMOP) Receptor Binding Assay

The hMOP receptor binding assay was performed as homogeneous SPA-assay(scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl(pH 7.4) supplemented with 0.052 mg/ml bovine serum albumin(Sigma-Aldrich Co. St. Louis. Mo.). The final assay volume (250 μl/well)included 1 nM of [N-allyl-2.3-³H]naloxone as ligand (PerkinElmer LifeSciences. Inc. Boston. Mass. USA) and either test compound in dilutionseries or 25 μM unlabelled naloxone for determination of unspecificbinding. The test compound was diluted with 25% DMSO in H₂O to yield afinal 0.5% DMSO concentration which also served as a respective vehiclecontrol. The assay was started by adding wheat germ agglutinin coatedSPA beads (GE Healthcare UK Ltd. Buckinghamshire. UK) which had beenpreloaded with hMOP receptor membranes (PerkinElmer Life Sciences. Inc.Boston. Mass. USA). After incubation for 90 minutes at RT andcentrifugation for 20 minutes at 500 rpm the signal rate was measured bymeans of a 1450 Microbeta Trilux ß-counter (PerkinElmer LifeSciences/Wallac. Turku. Finland). Half-maximal inhibitory concentration(IC50) values reflecting 50% displacement of [³H]naloxone-specificreceptor binding were calculated by nonlinear regression analysis and Kivalues were calculated by using the Cheng-Prusoff equation. (Cheng andPrusoff. 1973).

Human Kappa-Opioidpeptide (hKOP) Receptor Binding Assay

The hKOP receptor binding assay is run as homogeneous SPA-assay(scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl(pH 7.4) supplemented with 0.076 mg BSA/ml. The final assay volume of250 μl per well includes 2 nM of [³H]U69,593 as ligand, and either testcompound in dilution series or 100 μM unlabelled naloxone fordetermination of unspecific binding. The test compound is diluted with25% DMSO in H₂O to yield a final 0.5% DMSO concentration which serves asrespective vehicle control, as well. The assays are started by theaddition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250μl final assay volume per well) which has been preloaded for 15 minutesat room temperature with hKOP receptor membranes (14.8 μg/250 μl finalassay volume per well). After short mixing on a mini-shaker, themicrotiter plates are covered with a lid and the assay plates areincubated for 90 minutes at room temperature. After this incubation, themicrotiter plates are sealed with a topseal and centrifuged for 20minutes at 500 rpm. The signal rate is measured after a short delay of 5minutes by means of a 1450 Microbeta Trilux ß-counter (PerkinElmer LifeSciences/Wallac, Turku, Finland). Half-maximal inhibitory concentration(IC50) values reflecting 50% displacement of [³H]U69.593-specificreceptor binding are calculated by nonlinear regression analysis andK_(i) values are calculated by using the Cheng-Prusoff equation, (Chengand Prusoff, 1973).

Human Delta-Opioid Peptide (hDOP) Receptor Binding Assay

The hDOP receptor binding assay is performed as homogeneous SPA-assayusing the assay buffer 50 mM TRIS-HCl, 5 mM MgCl₂ (pH 7.4). The finalassay volume (250 μl/well) includes 1 nM of[Tyrosyl-3,5-³H]2-D-Ala-deltorphin II as ligand, and either testcompound in dilution series or 10 μM unlabelled naloxone fordetermination of unspecific binding. The test compound is diluted with25% DMSO in H₂O to yield a final 0.5% DMSO concentration which serves asrespective vehicle control, as well. The assays are started by theaddition of wheat germ agglutinin coated SPA beads (1 mg SPA beads/250μl final assay volume per well) which has been preloaded for 15 minutesat room temperature with hDOP receptor membranes (15.2 μg/250 μl finalassay volume per well). After short mixing on a mini-shaker, themicrotiter plates are covered with a lid and the assay plates areincubated for 120 minutes at room temperature and centrifuged for 20minutes at 500 rpm. The signal rate is measured by means of a 1450Microbeta Trilux ß-counter (PerkinElmer Life Sciences/Wallac, Turku,Finland). Half-maximal inhibitory concentration (IC50) values reflecting50% displacement of [Tyrosyl-3,5-³H]2-D-Ala-deltorphin II-specificreceptor binding are calculated by nonlinear regression analysis andK_(i) values are calculated by using the Cheng-Prusoff equation, (Chengand Prusoff, 1973).

Human Nociceptin/Orphanin FQ Peptide (hNOP) Receptor Binding Assay

The hNOP receptor binding assay was performed as homogeneous SPA-assay(scintillation proximity assay) using the assay buffer 50 mM TRIS-HCl,10 mM MgCl₂, 1 mM EDTA (pH 7.4). The final assay volume (250 μl/well)included 0.5 nM of [leucyl-³H]nociceptin as ligand (PerkinElmer LifeSciences. Inc. Boston. Mass. USA) and either test compound in dilutionseries or 1 μM unlabelled nociceptin for determination of unspecificbinding. The test compound was diluted with 25% DMSO in H₂O to yield afinal 0.5% DMSO concentration which also served as a respective vehiclecontrol. The assay was started by adding wheat germ agglutinin coatedSPA beads (GE Healthcare UK Ltd. Buckinghamshire. UK) which had beenpreloaded with hNOP receptor membranes (PerkinElmer Life Sciences. Inc.Boston. Mass. USA). After incubation for 60 minutes at RT andcentrifugation for 20 minutes at 500 rpm the signal rate was measured bymeans of a 1450 Microbeta Trilux ß-counter (PerkinElmer LifeSciences/Wallac. Turku. Finland). Half-maximal inhibitory concentration(IC50) values reflecting 50% displacement of [³H]nociceptin-specificreceptor binding were calculated by nonlinear regression analysis and Kivalues were calculated by using the Cheng-Prusoff equation. (Cheng andPrusoff. 1973).

hNOP Ki [nM] or % hMOP Ki [nM] or % Example inhibition at 1 μMinhibition at 1 μM SC-1 200 19% SC-2 850 12% SC-3 370 3605 SC-4 860 15SC-5 800 99 SC-6 1 285 SC-7 230 2 SC-8 3 100 SC-9 380 48 SC-10 2 157SC-11 99 3 SC-12 630 13% SC-13 860 18% SC-15 13 1330 SC-16 31 1315 SC-1855 805 SC-19 1810 5890 SC-20 1165 5840 SC-21 775 3580 SC-22 380 11%SC-23 25 545 SC-24 23 1185 SC-26 91 1015 SC-27 12 335 SC-28 46 78 SC-2916 65 SC-31 15 150 SC-32 36 100 SC-33 23 115 SC-34 17 50 SC-35 19 185SC-36 10 330 SC-37 37 44 SC-39 5 48 SC-40 6 102 SC-41 21 465 SC-42 21125 SC-43 31 83 SC-44 15 110 SC-45 25 37 SC-46 29 48 SC-47 9 44

Protocol for [³⁵S]GTPγS Functional NOP/MOP/KOP/DOP Assays

Cell membrane preparations of CHO-K1 cells transfected with the humanMOP receptor (Art.-No. RBHOMM) or the human DOP receptor(Art.-No.RBHODM), and HEK293 cells transfected with the human NOPreceptor (Art.-No.RBHORLM) or the human KOP receptor (Art.-No. 6110558)are available from PerkinElmer (Waltham, Mass.). Membranes from CHO-K1cells transfected with the human nociceptin/orphanin FQ peptide (hNOP)receptor (Art.-No. 93-0264C₂, DiscoveRx Corporation, Freemont, Calif.)are also used. [³⁵S]GTPγS (Art.-No. NEG030H; Lot-No. #0112, #0913, #1113calibrated to 46.25 TBq/mmol) is available from PerkinElmer (Waltham,Mass.).

The [³⁵S]GTPγS assays are carried out essentially as described by Gillenet al (2000). They are run as homogeneous scintillation proximity (SPA)assays in microtiter luminescence plates, where each well contains 1.5mg of WGA-coated SPA-beads. To test the agonistic activity of testcompounds on recombinant hNOP, hMOP, hDOP, and hKOP receptor expressingcell membranes from CHO-K1 or HEK293 cells, 10 or 5 μg membrane proteinper assay are incubated with 0.4 nM [³⁵S]GTPγS and serial concentrationsof receptor-specific agonists in buffer containing 20 mM HEPES pH 7.4,100 mM NaCl, 10 mM MgCl2, 1 mM EDTA, 1 mM dithiothreitol, 1.28 mM NaN₃,and 10 μM GDP for 45 min at room temperature. The microtiter plates arethen centrifuged for 10 min at 830 g to sediment the SPA beads. Themicrotiter plates are sealed and the bound radioactivity [cpm] isdetermined after a delay of 15 min by means of a 1450 Microbeta Trilux(PerkinElmer, Waltham, Mass.).

The unstimulated basal binding activity (UBS_(obs) [cpm]) is determinedfrom 12 unstimulated incubates and is set as 100% basal binding. Fordetermination of the potency and the efficacy, the arithmetic mean ofthe observed total [³⁵S]GTPγS binding (TB_(obs) [cpm]) of all incubates(duplicates) stimulated by the receptor-specific agonists (i.e. N/OFQ,SNC80, DAMGO, or U69,593) are transformed in percent total binding(TB_(obs) [%]) relative to the basal binding activity (i.e. 100%binding). The potency (EC₅₀) of the respective agonist and its maximalachievable total [³⁵S]GTPγS binding (TB_(calc) [%]) above its calculatedbasal binding (UBS_(calc) [%]) are determined from its transformed data(TB_(obs) [%]) by means of nonlinear regression analysis with XLfit foreach individual concentration series. Then the difference between thecalculated unstimulated [³⁵S]GTPγS binding (UBS_(calc) [%]) and themaximal achievable total [³⁵S]GTPγS binding (TB_(calc) [%]) by eachtested agonist is determined (i.e. B1_(calc) [%]). This difference(B1_(calc) [%]) as a measure of the maximal achievable enhancement of[³⁵S]GTPγS binding by a given agonist is used to calculate the relativeefficacy of test compounds versus the maximal achievable enhancement bya receptor-specific full agonist, e.g. N/OFQ (B1_(calc-N/OFQ) [%]) whichis set as 100% relative efficacy for the hNOP receptor. Likewise, thepercentage efficacies of test compounds at the hDOP, hMOP, or hKOPreceptor are determined versus the calculated maximal enhancement of[³⁵S]GTPγS binding by the full agonists SNC80 (B1_(calc-SNC80) [%]),DAMGO (B1_(calc-DAMGO) [%]) and U69,593 (B1_(calc-U69,593) [%]) whichare set as 100% relative efficacy at each receptor, respectively.

1. A compound according to general formula (I)

wherein R¹ and R² independently of one another mean —H; —C₁-C₆-alkyl,linear or branched, saturated or unsaturated, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —OH,—OCH₃, —CN and —CO₂CH₃; a 3-12-membered cycloalkyl moiety, saturated orunsaturated, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; whereinsaid 3-12-membered cycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted; or a 3-12-membered heterocycloalkyl moiety, saturated orunsaturated, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —OH, —OCH₃, —CN and —CO₂CH₃; whereinsaid 3-12-membered heterocycloalkyl moiety is optionally connectedthrough —C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted; or R¹ and R² together with the nitrogen atom to whichthey are attached form a ring and mean —(CH₂)₃₋₆—; —(CH₂)₂—O—(CH₂)₂—; or—(CH₂)₂—NR^(A)—(CH₂)₂—, wherein R^(A) means —H or —C₁-C₆-alkyl, linearor branched, saturated or unsaturated, unsubstituted or substituted withone, two, three or four substituents independently of one anotherselected from the group consisting of —F, —Cl, —Br and —I; R¹³ means—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; a 3-12-membered cycloalkylmoiety, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; a3-12-membered heterocycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; a 6-14-membered aryl moiety,unsubstituted, mono- or polysubstituted; wherein said 6-14-membered arylmoiety is optionally connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted; wherein said 5-14-membered heteroaryl moietyis optionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; R⁴means —H; —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said —C₁-C₆-alkyl isoptionally connected through —C(═O)—, —C(═O)O—, or —S(═O)₂—; a3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or—S(═O)₂—; a 3-12-membered heterocycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted; wherein said3-12-membered heterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; or wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through —C(═O)—,—C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; a 6-14-membered aryl moiety,unsubstituted, mono- or polysubstituted; wherein said 6-14-membered arylmoiety is optionally connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or wherein said 6-14-membered aryl moiety is optionallyconnected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; or a5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; orwherein said 5-14-membered heteroaryl moiety is optionally connectedthrough —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; R⁵ means —H;—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said —C₁-C₆-alkyl isoptionally connected through —C(═O)—, —C(═O)O—, or —S(═O)₂—; a3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted, mono- or polysubstituted; wherein said 3-12-memberedcycloalkyl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or—S(═O)₂—; a 3-12-membered heterocycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted; wherein said3-12-membered heterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; or wherein said 3-12-memberedheterocycloalkyl moiety is optionally connected through —C(═O)—,—C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; a 6-14-membered aryl moiety,unsubstituted, mono- or polysubstituted; wherein said 6-14-membered arylmoiety is optionally connected through —C₁-C₆-alkylene-, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or wherein said 6-14-membered aryl moiety is optionallyconnected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; or a5-14-membered heteroaryl moiety, unsubstituted, mono- orpolysubstituted; wherein said 5-14-membered heteroaryl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted, mono- or polysubstituted; orwherein said 5-14-membered heteroaryl moiety is optionally connectedthrough —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or —S(═O)₂—; R⁶, R⁷, R⁸, R⁹,R¹⁰, and R¹¹ independently of one another mean —H, —F, —Cl, —Br, —I,—OH, or —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; or R⁶ and R⁷ together mean ═O;wherein “mono- or polysubstituted” means that one or more hydrogen atomsare replaced by substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —R¹², —C(═O)R¹²,—C(═O)OR¹², —C(═O)NR¹²R¹³, —O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀—CH₃,═O, —OR¹², —OC(═O)R¹², —OC(═O)OR¹², —OC(═O)NR¹²R¹³, —NO₂, —NR¹²R¹³,—NR¹²—(CH₂)₁₋₆—C(═O)R¹³, —NR¹²—(CH₂)₁₋₆—C(═O)OR¹³,—NR¹⁴—(CH₂)₁₋₆—C(═O)NR¹²R¹³, —NR¹²C(═O)R¹³, —NR¹²C(═O)—OR¹³,—NR¹⁴C(═O)NR¹²R¹³, —NR¹²S(═O)₂R¹³, —SR¹², —S(═O)R¹², —S(═O)₂R¹²,—S(═O)₂OR¹², and —S(═O)₂NR¹²R¹³; wherein R¹², R¹³ and R¹⁴ independentlyof one another mean —H; —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, ═O, —OH, —NH₂, —NH—C₁-C₆-alkyl,—N(C₁-C₆-alkyl)₂, —C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —C(═O)OH,—C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NH—C₁-C₆-alkyl,—C(═O)N(C₁-C₆-alkyl)₂, —S—C₁-C₆-alkyl, —S(═O)—C₁-C₆-alkyl and—S(═O)₂—C₁-C₆-alkyl; a 3-12-membered cycloalkyl moiety, saturated orunsaturated, unsubstituted, mono- or polysubstituted; wherein said3-12-membered cycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, ═O, —OH, —NH₂, —NH—C₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂,—C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂,—C(═O)NH—C₁-C₆-alkyl, —C(═O)N(C₁-C₆-alkyl)₂, —S—C₁-C₆-alkyl,—S(═O)—C₁-C₆-alkyl and —S(═O)₂—C₁-C₆-alkyl; a 3-12-memberedheterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-or polysubstituted; wherein said 3-12-membered heterocycloalkyl moietyis optionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, ═O, —OH, —NH₂,—NH—C₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —C₁-C₆-alkyl, —O—C₁-C₆-alkyl,—C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NH—C₁-C₆-alkyl,—C(═O)N(C₁-C₆-alkyl)₂, —S—C₁-C₆-alkyl, —S(═O)—C₁-C₆-alkyl and—S(═O)₂—C₁-C₆-alkyl; a 6-14-membered aryl moiety, unsubstituted, mono-or polysubstituted; wherein said 6-14-membered aryl moiety is optionallyconnected through —C₁-C₆-alkylene-, linear or branched, saturated orunsaturated, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, ═O, —OH, —NH₂, —NH—C₁-C₆-alkyl,—N(C₁-C₆-alkyl)₂, —C₁-C₆-alkyl, —O—C₁-C₆-alkyl, —C(═O)OH,—C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NH—C₁-C₆-alkyl,—C(═O)N(C₁-C₆-alkyl)₂, —S—C₁-C₆-alkyl, —S(═O)—C₁-C₆-alkyl and—S(═O)₂—C₁-C₆-alkyl; or a 5-14-membered heteroaryl moiety,unsubstituted, mono- or polysubstituted; wherein said 5-14-memberedheteroaryl moiety is optionally connected through —C₁-C₆-alkylene-,linear or branched, saturated or unsaturated, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,═O, —OH, —NH₂, —NH—C₁-C₆-alkyl, —N(C₁-C₆-alkyl)₂, —C₁-C₆-alkyl,—O—C₁-C₆-alkyl, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)NH₂,—C(═O)NH—C₁-C₆-alkyl, —C(═O)N(C₁-C₆-alkyl)₂, —S—C₁-C₆-alkyl,—S(═O)—C₁-C₆-alkyl and —S(═O)₂—C₁-C₆-alkyl; or R¹² and R¹³ within—C(═O)NR¹²R¹³, —OC(═O)NR¹²R¹³, —NR¹²R¹³, —NR¹⁴—(CH₂)₁₋₆—C(═O)NR¹²R¹³,—NR¹⁴C(═O)—NR¹²R¹³, or —S(═O)₂NR¹²R¹³ together with the nitrogen atom towhich they are attached form a ring and mean —(CH₂)₃₋₆—;—(CH₂)₂—O—(CH₂)₂—; or —(CH₂)₂—NR^(B)—(CH₂)₂ ⁻, wherein R^(B) means —H or—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br and —I; or a physiologically acceptable salt thereof.
 2. Thecompound according to claim 1, wherein R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹independently of one another mean —H, —F, —OH, or —C₁-C₆-alkyl; or R⁶and R⁷ together mean ═O.
 3. The compound according to claim 1, whereinR¹ means —H; and R² means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted; R¹ means —CH₃; andR² means —C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; R¹ means —H or —CH₃; and R²means a 3-12-membered cycloalkyl moiety, saturated or unsaturated,unsubstituted; R¹ means —H or —CH₃; and R² means a 3-12-memberedcycloalkyl moiety, saturated or unsaturated, unsubstituted; wherein said3-12-membered cycloalkyl moiety is connected through —CH₂—,unsubstituted; or R¹ and R² together with the nitrogen atom to whichthey are attached form a ring and mean —(CH₂)₃₋₆—.
 4. The compoundaccording to claim 1, wherein R¹³ means —C₁-C₆-alkyl, linear orbranched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted.
 5. (canceled)
 6. The compound according to claim 1,wherein R¹³ means a 6-14-membered aryl moiety, unsubstituted, mono- orpolysubstituted, optionally connected through —C₁-C₆-alkylene-, linearor branched, saturated or unsaturated, unsubstituted.
 7. (canceled) 8.(canceled)
 9. (canceled)
 10. (canceled)
 11. The compound according toclaim 1, wherein R³ means a 5-14-membered heteroaryl moiety,unsubstituted, mono- or polysubstituted.
 12. (canceled)
 13. (canceled)14. The compound according to claim 1, wherein R¹³ means -phenyl,unsubstituted, mono-, di- or trisubstituted with —F, —Cl, —Br,—C₁-C₄-alkyl, —CF₃, —CHF₂, —CH₂F, —CN, —OH, —OC₁-C₄-alkyl, —OCF₃ or—OCH₂OCH₃; or -pyridinyl or thienyl, in each case unsubstituted, mono-,di- or trisubstituted with —F, —Cl, —Br, —C₁-C₄-alkyl, —CF₃, —CHF₂,—CH₂F, —CN, —OH, —OC₁-C₄-alkyl, —OCF₃ or —OCH₂OCH₃.
 15. (canceled) 16.(canceled)
 17. (canceled)
 18. (canceled)
 19. (canceled)
 20. (canceled)21. (canceled)
 22. (canceled)
 23. (canceled)
 24. (canceled) 25.(canceled)
 26. (canceled)
 27. (canceled)
 28. (canceled)
 29. (canceled)30. (canceled)
 31. The compound according to according to claim 1,wherein R⁴ means H; —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted; a 3-12-memberedcycloalkyl moiety, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; wherein the 3-12-membered cycloalkyl moiety isconnected through —C₁-C₆-alkylene-, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted; or a 3-12-memberedheterocycloalkyl moiety, saturated or unsaturated, unsubstituted, mono-or polysubstituted; wherein said 3-12-membered heterocycloalkyl moietyis connected through —C₁-C₆-alkylene-, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted.
 32. The compoundaccording to according to claim 1, wherein R⁴ means a 6-14-membered arylmoiety, unsubstituted, mono- or polysubstituted; wherein said6-14-membered aryl moiety is connected through —C₁-C₆-alkylene-, linearor branched, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; or a 5-14-membered heteroaryl moiety, unsubstituted,mono- or polysubstituted; wherein said 5-14-membered heteroaryl moietyis connected through —C₁-C₆-alkylene-, linear or branched, saturated orunsaturated, unsubstituted, mono- or polysubstituted.
 33. The compoundaccording to claim 1, wherein, R⁵ means —H.
 34. The compound accordingto claim 1, wherein R⁵ means —C₁-C₆-alkyl, linear or branched, saturatedor unsaturated, unsubstituted or substituted with one, two, three orfour substituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, —OH, —O—C₁-C₄-alkyl,—O—(CH₂CH₂—O)₁₋₃₀—H, —O—(CH₂CH₂—O)₁₋₃₀—CH₃, —C(═O)OH,—C(═O)OC₁-C₄-alkyl, —C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl,—C(═O)N(C₁-C₄-alkyl)₂, —S(═O)C₁-C₄-alkyl and —S(═O)₂C₁-C₄-alkyl. 35.(canceled)
 36. (canceled)
 37. (canceled)
 38. The compound according toclaim 1, wherein R⁵ means —C₁-C₆-alkyl, linear or branched, saturated orunsaturated, monosubstituted with a 3-12-membered heterocycloalkylmoiety, saturated or unsaturated, unsubstituted, mono- orpolysubstituted; wherein said 3-12-membered heterocycloalkyl moiety isoptionally connected through —C═O—.
 39. (canceled)
 40. (canceled) 41.The compound according to claim 1, wherein R⁵ means a 3-12-memberedcycloalkyl moiety, saturated or unsaturated, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,—OH, —C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —C₁-C₄-alkyl-OH, —O—(CH₂CH₂—O)₁₋₃₀—H,—O—(CH₂CH₂—O)₁₋₃₀—CH₃, —C(═O)OH, —C(═O)C₁-C₄-alkyl, —C(═O)OC₁-C₄-alkyl,—C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —NH₂,—NHC₁-C₄-alkyl, N(C₁-C₄-alkyl)₂, —NHC(═O)—C₁-C₄-alkyl,—N(C₁-C₄-alkyl)C(═O)C₁-C₄-alkyl, —S(═O)C₁-C₄-alkyl and—S(═O)₂C₁-C₄-alkyl; wherein said 3-12-membered cycloalkyl moiety isoptionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted.
 42. The compound according toclaim 1, wherein R⁵ means a 3-12-membered heterocycloalkyl moiety,saturated or unsaturated, unsubstituted or substituted with one, two,three or four substituents independently of one another selected fromthe group consisting of —F, —Cl, —Br, —I, —CN, —OH, —C₁-C₄-alkyl,—O—C₁-C₄-alkyl, —C₁-C₄-alkyl-OH, —O—(CH₂CH₂—O)₁₋₃₀—H,—O—(CH₂CH₂—O)₁₋₃₀—CH₃, —C(═O)OH, —C(═O)C₁-C₄-alkyl, —C(═O)OC₁-C₄-alkyl,—C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂, —NH₂,—NHC₁-C₄-alkyl, N(C₁-C₄-alkyl)₂, —NHC(═O)—C₁C₄-alkyl,—N(C₁-C₄-alkyl)C(═O)C₁-C₄-alkyl, —S(═O)C₁-C₄-alkyl and—S(═O)₂C₁-C₄-alkyl; wherein said 3-12-membered heterocycloalkyl moietyis optionally connected through —C₁-C₆-alkylene-, linear or branched,saturated or unsaturated, unsubstituted.
 43. (canceled)
 44. The compoundaccording to claim 1, wherein R⁵ means -phenyl, unsubstituted, mono- orpolysubstituted; wherein said phenyl is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted, mono- or polysubstituted; or wherein said phenyl isoptionally connected through —C(═O)—, —C(═O)O—, —C(═O)O—CH₂—, or—S(═O)₂—.
 45. (canceled)
 46. (canceled)
 47. (canceled)
 48. The compoundaccording to claim 1, wherein R⁵ means a bicyclic 9-10-memberedheteroaryl moiety, unsubstituted, mono- or polysubstituted. 49.(canceled)
 50. (canceled)
 51. (canceled)
 52. (canceled)
 53. The compoundaccording to claim 1, wherein R⁵ has a meaning selected from the groupconsisting of:


54. The compound according to claim 1, wherein R¹ means —H or —CH₃; R²means —C₁-C₆-alkyl, linear or branched, saturated, unsubstituted;-cyclopropyl; or -cyclopropylmethylene; or R¹ and R² together with thenitrogen atom to which they are attached form a ring and mean -azetidineor -pyrrolidine; R³ means -phenyl, -thienyl or -pyridinyl, in each caseunsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —CN, —C₁-C₄-alkyl, —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —OCF₃,—OH, —O—C₁-C₄-alkyl, —OCH₃, —C(═O)NH₂, C(═O)NHCH₃, —C(═O)N(CH₃)₂, —NH₂,—NHCH₃, —N(CH₃)₂, —NHC(═O)CH₃, —CH₂OH, SOCH₃ and SO₂CH₃; or R⁴ means —H;—C₁-C₆-alkyl, linear or branched, saturated, unsubstituted orsubstituted with one, two, three or four substituents independently ofone another selected from the group consisting of —F, —Cl, —Br, —I, —CN,—OH, ═O, —S(═O)₂—C₁-C₄-alkyl and —O—C₁-C₄-alkyl; 3-6-memberedcycloalkyl, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, —OH, and —O—C₁-C₄-alkyl, whereinsaid 3-6-membered cycloalkyl is connected through —C₁-C₆-alkylene;3-12-membered heterocycloalkyl, saturated or unsaturated, unsubstitutedor substituted with one, two, three or four substituents independentlyof one another selected from the group consisting of —F, —Cl, —Br, —I,—CN, —OH, and —O—C₁-C₄-alkyl; wherein said 3-12-memberedheterocycloalkyl is optionally connected through —C₁-C₆-alkylene-,unsubstituted or substituted with ═O; 6-14-membered aryl, unsubstitutedor substituted with one, two, three or four substituents independentlyof one another selected from the group consisting of —F, —Cl, —Br, —I,—CN, —OH, and —O—C₁-C₄-alkyl; wherein said 6-14-membered aryl isoptionally connected through —C₁-C₆-alkylene- or —S(═O)₂—; R⁵ means —H;—C₁-C₆-alkyl, linear or branched, saturated or unsaturated,unsubstituted or substituted with one, two, three or four substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —I, —CN, ═O, —OH, —O—C₁-C₄-alkyl, —O—(CH₂CH₂—O)₁₋₃₀—H,—O—(CH₂CH₂—O)₁₋₃₀—CH₃, —C(═O)OH, —C(═O)C₁-C₄-alkyl, —C(═O)OC₁-C₄-alkyl,—C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂,—(C═O)-heterocycloalkyl, —S(═O)C₁-C₄-alkyl, —S(═O)₂C₁-C₄-alkyl, —NH₂,—NH—C₁-C₄-alkyl, —N(C₁-C₄-alkyl)₂, —NHC(═O)—C₁-C₄-alkyl,—NH—S(═O)₂C₁-C₄-alkyl; 3-12-membered heterocycloalkyl, saturated orunsaturated, unsubstituted or substituted with one, two, three or foursubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —I, —CN, ═O, —OH, —C₁-C₄-alkyl, —NH₂,—NH—C_(I)—C₄-alkyl, —N(C₁-C₄-alkyl)₂, —NHC(═O)—C₁-C₄-alkyl,—NHS(═O)₂—C₁-C₄-alkyl, —O—C₁-C₄-alkyl, —O—(CH₂CH₂—O)₁₋₃₀—H,—O—(CH₂CH₂—O)₁₋₃₀—CH₃, —C(═O)OH, —C(═O)OC₁-C₄-alkyl, —C(═O)C₁-C₄-alkyl,—C(═O)NH₂, —C(═O)NHC₁-C₄-alkyl, —C(═O)N(C₁-C₄-alkyl)₂,—S(═O)C₁-C₄-alkyl, —S(═O)₂C₁-C₄-alkyl, -phenyl, —C(═O)-phenyl,—C(═O)-pyridyl, -pyridyl,-pyrimidinyl, and -pyridazinyl; wherein said3-12-membered heterocycloalkyl moiety is optionally connected through—C₁-C₆-alkylene-, linear or branched, saturated or unsaturated,unsubstituted; or wherein said 3-12-membered heterocycloalkyl moiety isoptionally connected through —C═O— or —CH₂—C═O—; -1,2-benzodioxole,-pyrazinyl, -pyridazinyl, -pyridinyl, -pyrimidinyl, -thienyl,imidazolyl, benzimidazolyl, -thiazolyl, -1,3,4-thiadiazolyl,-benzothiazolyl, -oxazolyl, benzoxazolyl, -pyrazolyl, quinolinyl,-isoquinolinyl, -quinazolinyl, -indolyl, -indolinyl,benzo[c][1,2,5]oxadiazolyl, imidazo[1,2-a]pyrazinyl, or-1H-pyrrolo[2,3-b]pyridinyl, in each case unsubstituted, mono- orpolysubstituted; and R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ mean —H; or R⁶ and R⁷together mean ═O and R⁸, R⁹, R¹⁰, and R¹¹ mean —H.
 55. (canceled) 56.(canceled)
 57. The compound according to claim 1, which is selected fromthe group consisting of2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetamide2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro-[3.4]-octan-6-one5-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)-4-methoxy-pyrimidine-2-carbonitrile5-(cyclobutylmethyl)-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one2-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetamide5-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)-4-methoxypyrimidine-2-carbonitrile2-(dimethylamino)-7-(4-methyl-2-morpholin-4-ylpyrimidin-5-yl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one7-(6-(azetidin-1-yl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one5-(2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methylpicolino-nitrile5-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methyl-picolinonitrile6-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-5-methyl-nicotinonitrile2-(dimethylamino)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]-octan-6-one5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one2-(dimethylamino)-7-(4-methyl-6-morpholinopyridin-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one2-(dimethylamino)-7-(6-(2-hydroxypropan-2-yl)-4-methylpyridin-3-yl)-2-phenyl-5,7-diazaspiro-[3.4]octan-6-one2-(dimethylamino)-7-(4-(2-hydroxypropan-2-yl)-2-methylphenyl)-2-phenyl-5,7-diazaspiro[3.4]-octan-6-one7-(6-(difluoromethyl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro-[3.4]octan-6-one2-(dimethylamino)-5-((3-fluorooxetan-3-yl)methyl)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)-pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one5-(cyclopropyl methyl)-7-(6-(difluoromethyl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-(3-fluoro-phenyl)-5,7-diazaspiro[3.4]octan-6-one2-(dimethylamino)-7-(2-morpholinopyrimidin-5-yl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one2-(dimethylamino)-5-((1-fluorocyclopropyl)methyl)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)-pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one2-(dimethylamino)-2-(3-fluorophenyl)-5-((1-hydroxycyclobutyl)methyl)-7-(5-(trifluoromethoxy)-pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-(2-hydroxypropan-2-yl)phenyl)-5,7-diazaspiro[3.4]octan-6-one2-(dimethylamino)-5-((3-fluorooxetan-3-yl)methyl)-2-phenyl-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,7-diazaspiro[3.4]octan-6-one5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(2-(methylsulfonyl)ethyl)-5,7-diazaspiro[3.4]octan-6-one5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-one5-(cyclopropylmethyl)-2-(dimethylamino)-7-((3-fluorooxetan-3-yl)methyl)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-one5-(cyclopropylmethyl)-7-(6-cyclopropylpyridin-3-yl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro-[3.4]octan-6-one7-(6-cyclopropyl-4-methylpyridin-3-yl)-5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one7-(6-cyclopropyl-4-methylpyridin-3-yl)-2-(dimethylamino)-5-((3-fluorooxetan-3-yl)methyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-one5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(2-methoxy-2-methylpropyl)-5,7-diazaspiro[3.4]octan-6-one2-(dimethylamino)-2-phenyl-7-(2-pyridin-4-ylpyrimidin-5-yl)-5,7-diazaspiro[3.4]octan-6-one5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-7-[5-(trifluoromethyl)pyridin-3-yl]-5,7-diazaspiro[3.4]octan-6-one5-[5-(cyclopropylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl]-3-(trifluoromethyl)pyridine-2-carbonitrile2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-morpholinobenzyl)-5,7-diazaspiro[3.4]octan-6-one5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-[(1-hydroxycyclobutyl)methyl]-5,7-diazaspiro[3.4]octan-6-one5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-7-(2-pyridin-4-ylpyrimidin-5-yl)-5,7-diaza-spiro[3.4]octan-6-one3-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)propanenitrile3-[5-(cyclopropylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl]-propanenitrile5-(cyclopropylmethyl)-2-(dimethylamino)-7-[(1-hydroxycyclobutyl)methyl]-2-phenyl-5,7-diaza-spiro[3.4]octan-6-one5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-[2-(oxetan-3-yl)ethyl]-5,7-diaza-spiro[3.4]octan-6-onecis-2-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)acetamidecis-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro-[3.4]octan-6-onecis-5-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)-4-methoxy-pyrimidine-2-carbonitriletrans-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro-[3.4]octan-6-onetrans-5-(2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)-4-methoxy-pyrimidine-2-carbonitrilecis-5-(cyclobutylmethyl)-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxo-ethyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-onetrans-5-(cyclobutylmethyl)-2-(dimethylamino)-7-(2-(1,1-dioxidothiomorpholino)-2-oxoethyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-onecis-2-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl-)acetamidetrans-2-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]-octan-7-yl)-acetamidecis-5-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl)-4-methoxypyrimidine-2-carbonitriletrans-5-(5-(cyclobutylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]-octan-7-yl)-4-methoxypyrimidine-2-carbonitrilecis-2-(dimethylamino)-7-(4-methyl-2-morpholin-4-ylpyrimidin-5-yl)-2-phenyl-5,7-diazaspiro-[3.4]octan-6-onecis-7-(6-(azetidin-1-yl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-onecis-5-(2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methyl-picolinonitrilecis-5-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-4-methylpicolinonitrilecis-6-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)-5-methylnicotinonitrilecis-2-(dimethylamino)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]-octan-6-onecis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-onecis-2-(dimethylamino)-7-(4-methyl-6-morpholinopyridin-3-yl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-onecis-2-(dimethylamino)-7-(6-(2-hydroxypropan-2-yl)-4-methylpyridin-3-yl)-2-phenyl-5,7-diazaspiro-[3.4]octan-6-onecis-2-(dimethylamino)-7-(4-(2-hydroxypropan-2-yl)-2-methylphenyl)-2-phenyl-5,7-diazaspiro-[3.4]octan-6-onecis-7-(6-(difluoromethyl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diaza-spiro[3.4]octan-6-onecis-2-(dimethylamino)-5-((3-fluorooxetan-3-yl)methyl)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)-pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-onecis-5-(cyclopropylmethyl)-7-(6-(difluoromethyl)-4-methylpyridin-3-yl)-2-(dimethylamino)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-onecis-2-(dimethylamino)-7-(2-morpholinopyrimidin-5-yl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-onecis-2-(dimethylamino)-5-((1-fluorocyclopropyl)methyl)-2-(3-fluorophenyl)-7-(5-(trifluoromethoxy)-pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-onecis-2-(dimethylamino)-2-(3-fluorophenyl)-5-((1-hydroxycyclobutyl)methyl)-7-(5-(trifluoromethoxy)-pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-onecis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-(2-hydroxypropan-2-yl)-phenyl)-5,7-diazaspiro[3.4]octan-6-onecis-2-(dimethylamino)-5-((3-fluorooxetan-3-yl)methyl)-2-phenyl-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-onecis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,7-diazaspiro[3.4]octan-6-onecis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(2-(methylsulfonyl)ethyl)-5,7-diazaspiro[3.4]octan-6-onecis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-7-(5-(trifluoromethoxy)pyridin-2-yl)-5,7-diazaspiro[3.4]octan-6-onecis-5-(cyclopropylmethyl)-2-(dimethylamino)-7-((3-fluorooxetan-3-yl)methyl)-2-(3-fluorophenyl)-5,7-diazaspiro[3.4]octan-6-onecis-5-(cyclopropyl methyl)-7-(6-cyclopropylpyridin-3-yl)-2-(dimethylamino)-2-phenyl-5,7-diaza-spiro[3.4]octan-6-onecis-7-(6-cyclopropyl-4-methylpyridin-3-yl)-5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-5,7-diazaspiro[3.4]octan-6-onecis-7-(6-cyclopropyl-4-methylpyridin-3-yl)-2-(dimethylamino)-5-((3-fluorooxetan-3-yl)methyl)-2-phenyl-5,7-diazaspiro[3.4]octan-6-onecis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-(2-methoxy-2-methylpropyl)-5,7-diazaspiro[3.4]octan-6-onecis-2-(dimethylamino)-2-phenyl-7-(2-pyridin-4-ylpyrimidin-5-yl)-5,7-diazaspiro[3.4]octan-6-onecis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-7-[5-(trifluoromethyl)pyridin-3-yl]-5,7-diazaspiro[3.4]octan-6-onecis-5-[5-(cyclopropylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl]-3-(trifluoromethyl)pyridine-2-carbonitrilecis-2-(dimethylamino)-2-(3-fluorophenyl)-7-(4-morpholinobenzyl)-5,7-diazaspiro[3.4]octan-6-onecis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-[(1-hydroxycyclobutyl)methyl]-5,7-diazaspiro[3.4]octan-6-onecis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-phenyl-7-(2-pyridin-4-ylpyrimidin-5-yl)-5,7-diazaspiro[3.4]octan-6-onecis-3-(5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-6-oxo-5,7-diazaspiro[3.4]octan-7-yl)propanenitrilecis-3-[5-(cyclopropylmethyl)-2-(dimethylamino)-6-oxo-2-phenyl-5,7-diazaspiro[3.4]octan-7-yl]-propane nitrilecis-5-(cyclopropylmethyl)-2-(dimethylamino)-7-[(1-hydroxycyclobutyl)methyl]-2-phenyl-5,7-diaza-spiro[3.4]octan-6-onecis-5-(cyclopropylmethyl)-2-(dimethylamino)-2-(3-fluorophenyl)-7-[2-(oxetan-3-yl)ethyl]-5,7-diaza-spiro[3.4]octan-6-oneand the physiologically acceptable salts thereof.
 58. (canceled)
 59. Amedicament comprising a compound according to claim
 1. 60. A method oftreating pain in a subject in need thereof, said method comprisingadministering to said subject an effective amount therefor of at leastone compound according to claim 1.